DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

FOOD AND DRUG ADMINISTRATION

 

CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

ANTI-INFECTIVE DRUGS ADVISORY

 

COMMITTEE (AIDAC) MEETING

 

 

 

Discussion of Issues Related to Clinical

Trial Design and Analysis in Studying Bacteremia

Due to Staphylococcus aureus and

Catheter Related Bacteremia

 

 

 

 

 

 

 

 

 

 

 

 

 

Thursday, October 14, 2004

 

8:20 a.m.

Hilton Gaithersburg

The Ballroom

620 Perry Parkway

Gaithersburg, Maryland


 

PARTICIPANTS

 

James E. Leggett, Jr., M.D., Chair

Shalini Jain, PA-C, MBA, Executive Secretary

 

MEMBERS

 

         Alan S. Cross, M.D.

         Celia J. Maxwell, M.D.

         Jan E. Patterson, M.D.

         Joan F. Hilton, Sc.D., MPH

         John S. Bradley, M.D.

         Donald M. Poretz, M.D.

         Samuel D. Maldonado, M.D., MPH

           (Industry Representative)

         John E. Edwards, Jr., M.D.

 

CONSULTANTS, SPECIAL GOVERNMENT EMPLOYEES (VOTING)

 

         Thomas R. Fleming, Ph.D.

         Christopher A. Ohl, M.D.

         L. Barth Reller, M.D.

         Nathan M. Theilman, M.D., MPH

 

CONSULTANT, FEDERAL EMPLOYEE (VOTING)

 

         Patrick R. Murray, Ph.D.

 

FDA

 

         Mark Goldberger, M.D.

         Sumathi Nambiar, M.D.

         John H. Powers, M.D.

         Alfred Sorbello, D.O.

         Janice Soreth, M.D.

C O N T E N T S

 

Call to Order and Opening Remarks:

         James E. Leggett, Jr., M.D.     5

 

Conflict of Interest Statement:

         Shalini Jain, PA-C, MBA         8

 

Opening Comments:

         Janice Soreth, M.D.            11

 

Regulatory History of Bacteremia Indications:

         Alfred Sorbello, D.O.          23

 

Questions from Committee                40

 

Epidemiology of S. aureus Bacteremia:

         Sumathi Nambiar, M.D.          55

 

Questions from Committee                74

 

Microbiological Considerations in Diagnosing

S. aureus Bacteremia:

         Patrick Murray, Ph.D.          82

 

Questions from Committee               103

 

Open Public Hearing--Extra Session     109

         Francis P. Tally, M.D.,

           Cubist Pharmaceuticals Inc.

 

Clinical Trials Issues with Studies of S. aureus

Bacteremia:

         John H. Powers, M.D.          131

 

Questions from Committee               173

 

Open Public Hearing    208

         Tim Henkel, M.D., Ph.D., Vicuron

         Pharmaceuticals               209

         Charles Knirsch, M.D., MPH, Pfizer

         Pharmaceuticals               222

        

         C O N T E N T S (Continued)

 

David Shlaes M.D., Ph.D., Idenix

Pharmaceuticals                        242

 

Issues in Studying Catheter-Related Bacteremia:

         Janice Pohlman, M.D.          247

 

Questions from Committee               269

 

Questions to Committee and Discussion 272

 

Summary  366


P R O C E E D I N G S

Call to Order and Opening Remarks

         DR. LEGGETT:  Good morning.  Today we are gathered to discuss issues related to clinical-trial design and analysis in studying bacteremia due to Staphylococcus aureus as well as issues related to clinical-trial design or analysis in studying catheter-related bacteremia.

         It is going to be, I hope, not a terribly eventful day but eventful, nonetheless.  I think that the problem that we are faced with, as clinicians, I faced on Friday when I was asked to see two patients, one a recently end-stage renal-disease patient with diabetes who has had three MRSA hemodialysis catheter infections since July when she started dialysis requiring the removal of the catheter and, at the same time, was called to see a patient because they had Gram-positive cocci in clusters from their one of two blood cultures and it turned out to be coagulate-negative Staph and who cared.

         So I think that is going to be sort of the crux of a lot of the problems today.

         To get started, why don't we go around the table and have everyone introduce themselves.

         DR. MAXWELL:  I'm Celia Maxwell, the Assistant Vice President for Health Sciences at Howard University, an adult infectious diseases specialist.

         DR. BRADLEY:  I am John Bradley, Pediatric Infectious Diseases, from Children's Hospital in San Diego.

         DR. OHL:  Chris Ohl, Section on Infectious Diseases, Wake Forest University School of Medicine.

         DR. HILTON:  Joan Hilton.  I am on the Biostatistics Faculty at University of California, San Francisco.

         DR. MURRAY:  Pat Murray, Director of Microbiology at the NIH Clinical Center.

         DR. RELLER:  Barth Reller, Division of Infectious Diseases and International Health and Director of Clinical Microbiology, Duke University Medical Center.

         DR. LEGGETT:  Jim Leggett, Infectious Diseases, Providence Portland Medical Center and the Oregon Health and  Sciences University.

         DR. CROSS:  Alan Cross, Center for Vaccine Development, University of Maryland.

         DR. FLEMING:  Thomas Fleming, Department of Biostatistics, University of Washington.

         DR. MALDONADO:  Sam Maldonado, Global and Regulatory Affairs, Johnson & Johnson.  I am the industry representative to this committee.

         DR. PATTERSON:  Jan Patterson, Medicine Infectious Diseases, University of Texas Health Science Center, San Antonio and South Texas Veterans Healthcare System.

         DR. THEILMAN:  Nathan Theilman, Division of Infectious Diseases and International Health, Duke University Medical Center.

         DR. PORETZ:  Donald Poretz, Infectious Diseases in Fairfax, Virginia.

         DR. NAMBIAR:  Sumathi Nambiar, Division of Anti-Infective Drug Products, FDA.

         DR. SORBELLO:  Fred Sorbello, Medical Officer, FDA.

         DR. POWERS:  John Powers, Lead Medical Officer for Antimicrobial Drug Development and Resistance Initiatives in ODE IV at FDA.

         DR. SORETH:  Good morning.  I am Janice Soreth, the Division Director for Anti-Infectives.  Let me take the opportunity to introduce in absentia our Office Director, Dr. Mark Goldberger, who is on his way.  But another person who is actually here and who directs a sister division, that of Special Pathogens and Immunologic Drugs which also regulates antibiotic development.  That would be Dr. Renata Albrecht who sits behind me here.

         MS. JAIN:  I am Shalini Jain, Executive Secretary for the Anti-Infective Drugs Advisory Committee.

Conflict of Interest Statement

         MS. JAIN:  Before we begin the meeting, I need to read a conflict-of-interest statement.  The following announcement addresses the issue of conflict of interest issues associated with this meeting and is made a part of the record to preclude even the appearance of such.

         Based on the agenda, it has been determined that the topics of today's meeting are issues of broad applicability and there are no products being approved.  Unlike issues before a committee in which a particular product is discussed, issues of broader applicability involve many industrial sponsors in academic institutions.

         All Special Government Employees have been screened for their financial interests as they may apply to the general topics at hand.  To determine if any conflict of interest existed, the agency has reviewed the agenda and all relevant financial interests as reported by the meeting participants.

         The Food and Drug Administration has granted general-matters waivers to the Special Government Employees participating in this meeting who require a waiver until Title 18 United States Code Section 208.  A copy of waiver statements may be obtained by submitted a written request to the agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

         Because general topics impact so many entities, it is not practical to recite all potential conflicts of interest as they may apply to each member, consultant and guest speaker.  FDA acknowledges that there may be potential conflicts of interest but, because of the general nature of the discussions before the committee, these potential conflicts are mitigated.

         With respect to FDA's invited industry representative, we would like to disclose that Dr. Samuel Maldonado is participating in this meeting as a non-voting industry representative acting on behalf of regulated industry.  Dr. Maldonado's role on this committee is to represent industry interests in general and not any one particular company.  Dr. Maldonado is employed by Johnson & Johnson.

         In the event that the discussions involve any other products or firms not already on the agenda for which FDA participants has a financial interest, the participants' involvement and their exclusion will be noted for the record.

         With respect to all other participants, we ask, in the interest of fairness, that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they may wish to comment upon.

         Thank you.

         DR. LEGGETT:  Janice, would you like to start?

Opening Comments

         DR. SORETH:  Good morning, Dr. Leggett and special thanks for the academic quarter this morning, members of the advisory committee, FDA and industry colleagues and other members of the audience.

         (Slide.)

         I would like to begin today's talks by telling you what we are going to talk about today followed by actually talking about it, then summarizing what we already told you as a segue to the discussion.  I promise we will finish before midnight.

         This is the story of blood and guidance going a bit bad, that of bacteremia as an indication.

         (Slide.)

         I am going to take us first through the District of Columbia, Rockville and White Oak--you will understand what I mean in just a moment--followed by a tour, very briefly, of Hollywood, the Washington Redskins, the NHL lockout, Monday morning quarterbacking--that would be the discussion period--and wrapping up with credits.  I promise you I have not yet lost my mind.

         (Slide.)

         We are back in the District of Columbia.  It is pre-1965.  I am in second grade.  We have been talking about bacteremia, sepsis, bacteremic sepsis, septicemia, primary bacteremia and secondary bacteremia for a long, long time, ever since the FDA was solely located in the District.

         As far as the Org chart goes back then, and this is all oral history, we were the Bureau of Biological and Physical Sciences, the Division of Pharmacology and we were a branch, I think, of Antibiotics.  As I said, my knowledge of this era is entirely derivative.

         (Slide.)

         Let's fast-forward to Rockville of the '70s and the '80s where the language for bacteremia and septicemia began to make it into package inserts.  We will hear more about this historical framework and its details through to the 1990s and the present from Dr. Fred Sorbello this morning.

         The Org chart was changing.  We were becoming the Bureau of Biological and Physical Sciences, Division of Pharmacology to the Bureau of Drugs and Biologics, Division of Anti-Infective and, finally, the Center for Drug Evaluation and Research.  I realize only now I forgot to put Crystal City on there because, once we went from the District, we went to Crystal City which is in Virginia and then, ultimately, to Rockville and Gaithersburg, which is where we are now.

         The Division was morphing at the same time.  It was growing.  Back in the '70s and '80s, we were the Division of Anti-Infectives.  We were one entity that took care of regulation of antibiotics, anti-infectives, anti-parasitics, topical antiseptics, dermatologics, ophthalmologics, anti-fungals, T.B. drugs and antivirals.  I am sure I left something out.  Let me know at the break.

         There was a split, then, that happened in the latter '80s.  I think it was about '88 when the development of HIV therapies took off, as it should.  So we split and became the Division of Antiviral Drugs as well as the Division of Anti-Infectives.  The Antiviral therapies together with the Antifungals and the TB drugs, then, went to the Division of Antivirals.

         This is the late '80's, early '90's.

         (Slide.)

         By the time we hit mid-'90's, maybe about 1996, we, as two divisions, were large again.  Portfolios were growing.  So we decided to morph at that point into a third division.  So the Ur-Division, as I like to call it, of Anti-Infectives then became Anti-Infectives, Antivirals and Special Pathogens and Immunologic Drug Products directed by Dr. Renata Albrecht.

         The portfolio from Anti-Infectives of quinolones split off to Special Pathogens.  I believe chronic fatigue and AIDS wasting type of drugs and transplant products and antifungals and antiparasitics also went to Special Pathogens.

         So we are now three divisions under the leadership of Dr. Mark Goldberger.  It is pertinent--the background is pertinent to today because the topics really touch all of us within the office and particularly Anti-Infectives and Special Pathogens.  We need to be careful as we write the music that we sing from the same sheet of music.

         I think more on the history of what we have struggled with as a word, bacteremia, septicemia, will be discussed later today not only by Dr. Fred Sorbello but also, in terms of clinical-trial design considerations by Dr. John Powers, by Dr. Janice Pohlman as well as Dr. Sumathi Nambiar.

         (Slide.)

         As to the future, we are moving in 2005, we are told, to White Oak.  Shalini, correct me if I am wrong, but I think all that AC meetings will take place there.

         MS. JAIN:  Actually no.  They won't be able to actually accommodate the size.

         DR. SORETH:  Wonderful.  Okay.  To be determined later.  Shalini was just saying that we won't necessarily have the AC meetings at White Oak.  It is our combined campus, a dream that we have maintained at FDA for a long, long time.  Some would say a nightmare, but whatever.   It is off New Hampshire around the Beltway for Washingtonians.

         This is the laboratory building.  Our building is off to that side.  I am a little challenged directionally.  I would submit to you that we sincerely hope to have the guidance in this arena tucked away by the time we move to White Oak.  So, see, we have a challenge.

         (Slide.)

         Hollywood, where we are told nothing is impossible, where every scientist should remove the word "impossible" from his lexicon.  Christopher Reeve.  Nothing is impossible.

         (Slide.)

         Except maybe when it comes to the breakdown of skin, invasion of the blood stream and infection of the patient followed by cardiac arrest, heart failure, coma and death, for Superman was no match for a bloodstream infection.

         (Slide.)

         I think our meeting today will highlight that it takes extraordinary individuals to recognize that investment and effort in the discovery of new antibiotics and in the treatments for serious infections, like Staphylococcus aureus bacteremia, are indeed worth it in the long run.  And I know that some of these extraordinary individuals are in this room today.

         They are prescribing physicians.  They are academicians.  They are industry colleagues.  They are FDA colleagues.  They are support staff all of whom have, at heart, the same mission.

         (Slide.)

         So what do the Skins have to do with this?  Well, you have to ask yourself the question what do Joe Gibbs, who is the Head Coach of the Washington Redskins, and the FDA have in common?  I will preface my comments by saying I am a die-hard Eagles fan but it is not why I say this.

         Just like Joe Gibbs, we thought we had put all the right pieces together on the team with the catheter-related blood-stream infection guidance.  That is 1999 and Dr. Janice Pohlman will tell us a lot more about that later today.  And, just like Joe Gibbs, we watched as the monster just wouldn't get up.

         (Slide.)

         We discussed the catheter-related blood-stream infection guidance hereafter known as CRBSI at a 1999 advisory committee meeting.  Most of you were probably not here then because we had a different committee there.  But I know Dr. Barth Reller was there.  The U.S. stats would tell us that roughly there are 200,000 or 400,000 episodes per year.  We should be able to study it.

         Mortality attributable somewhere between 10, 25 percent; we thought a definable case definition--we thought.  Lo and behold, sponsors, many of them, now tell us there are numerous reasons why they have hit the boards.  But I would ask, don't blame it on my heart; blame it on my youth.

         (Slide.)

         The NHL lockout is pertinent here because success, beyond being tied to this year's salary cap, is determined not by knowing where the puck is, rather knowing where the puck is going to be, which is sometimes, maybe often, unpredictable which is probably why they don't want a salary cap in the first place.  But the increasing incidence of Staph aureus bacteremia paralleled by a rise in infective endocarditis, I think, foreshadows where major players need to position themselves to win, to develop effective therapies whose risk/benefit ratio we think we understand so that, ultimately, patients and their prescribing physicians can benefit from this.

         (Slide.)

         The issues for discussion are many.  Dr. John Powers will cover these in great detail.  I have made some excerpts and highlights from his talk that will come later today.  But I want you to bear them in mind as you go through today's discussions and talks.  Should primary bacteremia due to Staph aureus, PBSA, be an indication?  And what exactly would a healthy development program look like?  What patient populations would be included in such a program?

         And, just as importantly, would there be populations that should be excluded, because we are not really sure they have an infection?  Do they have a lab finding?  Should endocarditis due to Staph aureus be a separate indication?

         (Slide.)

         More issues for discussion.  Should we grant a separate catheter-related blood-stream infection indication in its own right?  Does it have merit?  Does it lack merit?  Or, do we fold it into a more general clinical-trial experience and product label under the rubric of primary bacteremia due to Staph aureus or under the rubric of complicated skin infections?

         If we go the separate way, what additional information would you suggest be collected before, or while, treating other serious Staph aureus infections?

         (Slide.)

         Finally, what role do preclinical and early clinical studies play in setting the stage for faster, larger clinical trials?  We are cognizant of the fact that, in many ways, in drug development, as in life, time and money are our enemies.  We sweat the small stuff and we ask you today to do the same.

         How many positive blood cultures are required prior to entry into a primary bacteremia due to Staph aureus clinical trial?

         (Slide.)

         Last, screening patients for admission into these clinical trials appears to be complicated.  Do you have any thoughts or advice for us as to a general approach?

         (Slide.)

         I would like to thank Shalini Jain, our Exec Sec contact and organizer for today's meeting who answered numerous phone calls, E-mails and cell-phone calls way later than anyone should have made them, myself included; our Office Director, Mark Goldberger; John Powers; Ed Cox: and Leo Chan; and, at the Division level, my ever supportive reliable deputy, Lilian Gravrilovich and members of the division, Sumathi Nambiar, Janice Pohlman and Fred Sorbello.

         I will stop there and turn the podium back over to Dr. Leggett.

         DR. LEGGETT:  Thank you.

         Let's move on to the Regulatory History of Bacteremia Indications which will be done by Dr. Sorbello.

Regulatory History of Bacteremia Indications

         DR. SORBELLO:  Good morning.  I am Fred Sorbello, Medical Officer at the Division of Anti-Infective Drug Products at FDA.

         (Slide.)

         My presentation today will focus on the regulatory history of bacteremia and some of the early regulatory history of catheter-related blood-stream infections as labeled blood-stream infection indications.

         (Slide.)

         I wanted to start with an historical time line to help to focus a little bit on the history of the development of this whole issue from a regulatory perspective.  It really began prior to 1992, 1993.  As Dr. Soreth had described, there were various types of terminology that were being used in the setting of labeling for blood-stream infections.

         In 1992, the FDA developed a document called Points to Consider.  This was a very important document because it was designed to assist investigators on how to formulate drug-development plans for infective agents.  Since that time, there have been several anti-infective drug advisory committee meeting where the issue has been discussed, including 1993, 1998 and 1999 and, obviously, at the meeting today.

         (Slide.)

         Just to give you a little bit of a perspective on the terminology that has been used for blood-stream infections in antimicrobial, I just have a chart to kind of compare the historical terminology versus what is used currently.  Historically, labels would include terms such as bacteremia or septicemia or bacteremia/septicemia, bacterial septicemia or septicemia (including bacteremia.)

         Today, what is used currently is terminology that is in accordance with the Points to Consider document which is basically site-specific indications with bacteremia included if bacteremic patients were involved and assessed adequately within the particular trials.

         To give you a little more perspective on the labeling indications prior to 1992, 1993, the terms "bacteremia" and "septicemia" were those that were used most commonly.  These were defined as infections that were accompanied by certain types of laboratory criteria.

         Bacteremia related to the evidence of one positive blood culture, septicemia with two positive blood cultures.  It is important to note that, at that time, there were no specific clinical-trial protocols that were really relevant to those indications.  The data was derived by pooling data on bacteremic patients from trials that involved different sites of infection; for example, trials that might have looked at pneumonia or urinary-tract infections where bacteremic patients may have been enrolled.

         Also the clinical context was bit varied in that patients with either transient bacteremias or, as I mentioned, bacteremias where there may be an identifiable focus or even bacteremias of unknown origin could have been included amongst this pooled data.

         (Slide.)

         1992, Points to Consider, a very critical document that was developed.  Again, it did contain relevant information on the agency's perspective on specific indications for anti-infective drugs.  It really was an attempt to recognize that different types of infections had different pathophysiology.

         The way labeled indications were indicated was they were referred to as the treatment of an infection at a specific body site due to a specified susceptible microorganism.  Drug-development guidelines were provided with the document so that accurate information could be complied on both the efficacy and safety of the drug and that information could later be described in product labeling.

         (Slide.)

         The 1993 Anti-Infective Drug Advisory Committee focused a bit on this issue of bacteremia in the setting of two issues.  Number one, the consensus document developed by the American College of Chest Physicians and the Society of Critical Care Medicine where definitions were published regarding terms such as sepsis and multi-organ failure.  In addition, a pharmaceutical sponsor had proposed a new indication termed bacteremic sepsis in an attempt to try to both add some specificity and clarify some of the previous terminology in order to do a particular drug-development study.  The definition of bacteremic sepsis included some of the material from the consensus document.

         (Slide.)

         Just to review briefly the consensus-document definitions, infection was described as a microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion or normally sterile host tissue by those organisms.

         Bacteremia was defined as a laboratory finding associated with the presence of viable bacteremia in the blood.  The systemic inflammatory response was a response that can occur with a multitude of clinical entities and it was basically manifested by two or more of the criteria that were listed which was temperature greater than 30 degrees C or less than 36 degrees C, an elevated heart rate of greater than 90 beats per minute, respiratory rate greater than 20 beats per minute or a PA-CO2 of less than 32, an elevated white count of 12,000 or a low white-blood count of less than 4,000 or 10 percent bands.

         Sepsis, then, was defined as an infected patient who exhibited a systemic inflammatory response.

         (Slide.)

         This is a Venn diagram which is adapted from the paper in Critical Care Medicine which described the consensus document in the definitions.  But it was an attempt to try to show how some of these concepts merge, again illustrating that there is a large focus of infected patients and some of those patients will exhibit a systemic inflammatory response syndrome.  Those that do are considered septic.

         Bacteremia essentially refers to the laboratory finding of bacteremia in a blood culture.  Again, just keep in mind that there can be other non-infectious causes that can produce a systemic inflammatory response including burns, ischemia, pancreatitis and others.

         (Slide.)

         So, getting back to bacteremic sepsis with the consensus definitions and concepts in mind, bacteremic sepsis was defined at the time as SIRS, systemic inflammatory response syndrome, due to an infection that was associated with positive blood cultures but was without hypotension, hypoperfusion or any evidence of organ dysfunction.

         The definition implied, but it didn't state, that the patient would have an identifiable focus of infection.  Now, when this concept was discussed by the 1993 Anti-Infective Drug Advisory Committee, there were a number of issues that were reviewed.  I am just going to mention some of them here at this point.

         One is bacteremic sepsis really a clinically meaningful entity.  Could we, really, on a clinical basis, identify patients who had that entity.  Number two, there were concerns that the population would be rather heterogeneous because you might be looking at patients with different types of underlying diseases, different states of immunosuppression, immunocompetence, for instance.

         Positive blood cultures; it was certainly felt that they do add confirmation and specificity in identifying an infecting organism but there was some discussion about whether positive blood cultures could, in some way, be a marker of prognosis.

         Another issue was the efficacy of a drug in treating a blood-stream infection and whether it would be possible to extrapolate the efficacy in clearing a blood-stream infection to being comparable effective in treating an infection that is, for example, deep within a certain body tissue or site that might be the source for that bacteremia.

         (Slide.)

         So, amongst the discussion at the time in 1993, it was felt that the terms bacteremia and septicemia as had been used lacked specificity of definition.  Again, there were concerns about the patient populations that would be studied.  There were concerns about the whole concept of pooling data from various sites of origin, effective origin for bacteremias and, lastly, whether or not it would be possible on a clinical basis to actually identify a person who had sepsis infection with a systemic inflammatory response who would have a positive blood culture versus those who would have clinical findings without a positive blood culture, was it really clinically meaningful and could it be identified on the clinical basis.

         (Slide.)

         The recommendations from the Anti-Infective Drug Advisory Committee at the time in '93 was, again, to focus labeling related to the site of infection, site-specific labeling as had been described through the Points to Consider Document and then including bacteremia within that context if it was applicable rather than using terms such as bacteremia or bacteremic sepsis.

         (Slide.)

         Now over the following five years, there were no new drugs that had been approved with the indication of bacteremia.  But bacteremia and this whole concept of blood-stream-infection indications resurfaced again back in 1998 at the Anti-Infective Drug Advisory Committee.

         In particular, the main topic referred to catheter-related blood-stream infections.  The issues that brought the issue up for discussion included the observed rising incidence of bacteremia due to resistant Gram-positive bacteria in particular, the increased incidence that was noted of intravenous catheter-related bacteremia and well as bacteremia without an identifiable focus and the whole concept of how to really utilize data from bacteremic patients in order to analyze and supplement clinical-trials data since there were really no clinical trials directly developed with protocols to look at bacteremia specifically.

         (Slide.)

         Regarding the issue of bacteremia as an indication, the committee reaffirmed, again, using the concept of site-specific labeling for secondary bacteremias but also had some discussion about the concept of a primary bacteremia as a potential new indication and a fair amount of discussion focusing, again, on catheter-related blood-stream infections, catheter-related blood-stream bacteremias as a focus for future studies and potentially an area for future drug development.

         (Slide.)

         To give some follow up regarding the committee's thoughts on catheter-related blood-stream infections, the issues, again, of the increased incidence of those types of infections that were noted, the problems of growing antimicrobial resistance and also the limited antimicrobial armamentarium that would be available for treatment, but also the lack of the controlled clinical trials for drug development for agents to treat path-related blood-stream infections.

         There were a number of topics that were discussed including issues of what types of criteria should there be for catheter removal, what types of both clinical and microbiologic criteria should be considered, the number and the source of blood cultures for this potential indication as well as what types of laboratory studies might be considered to verify concordance of blood culture and catheter culture isolates such as DNA subtyping was discussed for Staphylococcus epidermidis.

         (Slide.)

         So, following the Anti-Infective Drug Advisory Committee meeting in '98, a working group was formulated at FDA, the CRBSI Working Group, and a draft guidance was developed regarding drug development for catheter-related blood-stream infections.  This guidance was then presented the following year at the 1999 Anti-Infective Drug Advisory Committee meeting.

         (Slide.)

         There was extensive discussion about the draft guidance and a number of issues were mentioned.  I just wanted to point out some of these discussion issues because I think they are very pertinent to today's discussion and a number of them are, as yet, undefined and not clearly resolved.

         Number one was the issue of a heterogenous patient population, again the concept that, looking at catheter-related blood-stream infections you would potentially be looking at a large population of patients, different types of underlying diseases, different types of catheters, tunnel/non-tunnel, short-term/long-term, and a whole variety of potentially causative microorganisms.

         Number two was the sample size that might be required.  Again, the thought was it may require a number of patients to screen to actually identify those who were felt to have a catheter-related blood-stream infection.  In particular, there were concerns, and in studies such as this, it would be important to get catheter data, if catheters are indwelling in the patient and what is more frequently done is they are just pulled and discarded  without being cultured, the lack of catheter data may be a limiting finding.

         The other issue is the concept of doing microbiologic evaluation and test-of-cure; is it necessary, what situations would it be necessary and would the lack of test-of-cure microdata, again, limit evaluation of this type of a study.

         There were also concerns about the lack of a standardized disease definition for catheter-related blood-stream infection and also the lack of demonstrable treatment effect for certain types of organisms, especially organisms that are low virulence that are associated with skin sites such as coag-negative Staph, Bacillus, Corynebacterium, some of those types of bacteria.

         (Slide.)

         Another main area was the lack of standardized procedures as to how to manage an infected catheter.  It was recognized that there was basically a lack of standard criteria to provide proof of a catheter infection, should the types of cultures be catheter-drawn and peripherally blood-drawn blood cultures, should it be based on two blood cultures, should it be based on quantitative catheter tips, hub cultures.  A number of different options were discussed without any apparent consensus.

         The other issue is, in management, what would be the criteria to remove the catheter since it was recognized that patients can have different types of catheters that can be in for different periods of time and also you can have different infecting microorganisms as there was some discussion of organisms such as Staphylococcus epidermidis that may not always require removal of the catheter.  Again, what types of criteria should be thought about in trying to address the catheter-removal issue.

         (Slide.)

         Last, microbiological issues that were discussed and I alluded to these a little bit.  Number one, the issue of quantitative blood cultures and the fact that they are rather limited in their availability.  Most hospitals are not able to do quantitative blood cultures and what would be some other options to take a look at.  One that was mentioned was the possibility of looking at differential blood-culture time-to-positivity.

         Again, concordance of catheter and blood-culture isolates, what type of catheter-related isolates would be felt to be valid and how would it be possible to document that there would be concordance and, again, certain types of coagulase-negative Staph would probably be organisms where that would be an important issue.

         As I alluded to previously the concept of test-of-cure blood cultures; do you need to do a test-of-cure blood culture in someone who studied in the context of the clinical trial for a catheter-related blood-stream infection.  If the patient is well and stable and doing fine, is that really a requirement or should it be reserved basically as a secondary endpoint for patients where the catheter is retained and they are basically treated through.

         (Slide.)

         So, in summary, I have tried to summarize for you the regulatory history of bacteremia and some of the early developmental history regarding catheter-related blood-stream infections.  I have tried to hit on some points such as the revisions and the changes that have occurred in terminology that has been used in labeling, the Points to Consider document which has the label-indication concept as basically what is employed currently and some of the multiple issues that have been discussed at previous Anti-Infective Drug Advisory Committees in attempting to discuss and grapple with a lot of the issues about how to study bacteremia, catheter-related infections and what some of the appropriate criteria will be.

         This afternoon, Dr. Janice Pohlman is going to provide some additional historical and current perspectives on catheter-related blood-stream infections, in much greater detail provide more recent information to you.

         Thank you for your attention.

         DR. LEGGETT:  Thank you, Dr. Sorbello.

Questions from Committee

         Does anyone have any questions?  Don?

         DR. PORETZ:  I imagine that the majority of these patients are hospitalized but not all of them.  There are certainly plenty of patients who have cultures obtained on an outpatient basis and are treated on an outpatient basis.  But, if a patient is in the hospital, when they are discharged, the diagnoses are put on the front of the chart and coded.  Is that information accurate many times and who has access to that information, and when you are trying to figure out the total number of these patients, is there a central way that information is gathered?  Can you explain that me?

         DR. SORBELLO:  I don't know that there would be a central clearing house or anything for that type of information.

         DR. PORETZ:  Does anyone know?

         DR. SORBELLO:  I don't know.

         DR. POWERS:  Are you asking about ICD9 codes and their use in diagnosis?

         DR. PORETZ:  Yes, essentially.  Where does that information--does it get entered somewhere?

         DR. POWERS:  In terms of for us to use, the FDA to use?

         DR. PORETZ:  Central reporting group.

         DR. POWERS:  No; we have actually gone--Janice, you may want to add to this, but we have actually had to go and actually pay to get that data from people like large HMOs and other folks to be able to actually collate that information.  However, the CDC has done some studies on the accuracy or lack of accuracy with some of these diagnoses.

         The probably with ICD9 codes is they are used for billing and people often code them in terms of the highest amount that they can bill for so that the accuracy sometimes is not 100 percent, certainly not to the level, the specificity, we would like in terms of enrolling people in a clinical trial.

         Janice, do you want to add something?

         DR. POHLMAN:  You know, I did look into this and was going to speak to this a little bit in the afternoon, but I think largely the numbers that are in the literature, you know, you get this wide range--I tried to look for the ICD9 codes or, I guess, we are heading towards ICD10.  It is really hard to--they are not coded specifically for that.  A lot of the numbers come from nosocomial surveillance systems that actually may miss patients that are treated in an outpatient arena as some of these patients don't even get hospitalized when the bacteremia is discovered as well as patients that--some of the surveillance systems will just pick up--it depends on how the hospital is doing surveillance on whether or not they are doing non-critical-care units.  It may just be they are getting critical-care numbers so the estimates are really subject to a lot of variation.

         DR. LEGGETT:  Alan?

         DR. CROSS:  At one point, the arguments in the infectious-disease community were really on, for example, the length of therapy for Staph aureus bacteremia based on whether or not there was either a non-removable or removable focus.  It sounds like, going through your discussion, that really was never a viable discussion.

         I think if one thinks back on that type of discussion, obviously catheter-related infections would be a subset of removable foci.  On the other hand, the nonremovable focus would encompass Staph aureus bacteremia of a multitude of primary foci, whether it was from the skin, the urine or elsewhere.

         That has never entered into any of the discussions, it sounds like.

         DR. SORBELLO:  There had been some discussions about treatment although there was not a great focus on duration of treatment.  I think part of that was because of the discussion about how do you really manage the catheter?  Who do you identify and can you identify some type of uniform guidelines of who has a catheter removed, what kind of catheters remain; is it related to the type of organism; do you treat them differently if you keep the catheter in versus you take the catheter out.

         So it had been discussed but I think it was kind of folded into some of the other more structural constructs of how to really go about formulating some type of, if you could, a uniform management guideline for catheters.

         DR. CROSS:  But, looking at the other end of it, though, of the nonremovable foci, it sounds like a discussion of the origin of the bacteremia seemed to make a difference in terms of the recommendations.  I don't know whether there is any data presented at those meetings to actually support that point of view.

         DR. SORBELLO:  Not specific data that I remember from the transcripts but, again, the previous Anti-Infective Drug Advisory Committees felt, overall, that going with site-specific indications and then tying the terminology of bacteremia to an identifiable focus was most appropriate for labeling.

         I think part of grappling with catheter-related infections was there was really no standardized uniform accepted definition of what a catheter-related infection was let alone best management because everybody has somewhat of a different way to kind of tailor their approach, again depending on the organism, the type of catheter, the type of patient.

         So I think treatment is an extremely important aspect of all this and I think it really folds in as a very important aspect of management.  But I think some of the other constructs of actually how to put the clinical trial together and develop a population appeared to be somewhat more of a priority in the prior discussions.

         DR. LEGGETT:  It has also been a moving target looking at the new drugs we have looked at that are treating five days for pneumonia, et cetera.

         Chris?

         DR. OHL:  Could you outline how the discussions went parallel to all of--in this time line related to endocarditis and diagnosis of endocarditis for trials?

         DR. SORBELLO:  Actually, there was not much discussed regarding endocarditis at the prior Anti-Infective Drug Advisory Committee meetings as far as criteria for a clinical trial, criteria for labeling.  There was not really an in-depth discussion about that.

         As I say, the '93 Anti-Infective Drug Advisory Committee meeting was basically grappling with the new definitions that were published of how do you define what sepsis is, how do you fit that in to the clinical setting and how do you tie that in, then, to the labeled indications that were used at the time which were bacteremia and septicemia where there was still a lot of confusion and discussion about whether they are specific enough and appropriate enough for a label.

         But there was not really an in-depth discussion about endocarditis as an indication.

         DR. LEGGETT:  Jan?

         DR. PATTERSON:  I wonder if you could clarify for me what we mean when we say primary bacteremia because, as a hospital epidemiologist, in doing nosocomial infection surveillance, when we look for catheter-related infections, we want to make sure that there is not another identifiable site so that it is not a secondary infection.

         So we call it a catheter-related infection and sometimes we even use the term primary bacteremia.  With Staph aureus, as clinicians, we very often find a source, whether it is endocarditis or an abscess or the catheter.  So I am just wondering if you could clarify for me what we mean by primary bacteremia versus catheter-related.

         DR. SORBELLO:  The context that those terms were used in the historical setting was the primary bacteremia either referred to the patient with endocarditis or the catheter-related infection and that bacteremias, secondary bacteremias, were where you had some other identifiable focus, whether it was along with the urinary tract or whatever.

         But primary bacteremia in the historical sense here was used either in the setting of endocarditis or catheter-related.

         DR. LEGGETT:  Barth?

         DR. RELLER:  I have had the great privilege of actually, I think, being at every one of the meetings that Dr. Sorbello--and the comment that I wanted to make was that he has done a masterful and accurate capture of the essence of that decade.

         I think history is very important if we are to learn from it.  And a few additions.  Dr. Cross brought up the question of role of removal.  In fact, that has been discussed because--not that the answers are in, but the discussion, because the recognition that removal is of varying degrees of facility in importance in the outcome but must be considered and that was captured here; that is, whether it is a peripheral catheter, indwelling, tunneled, et cetera, and also the organism and the interplay between the organism so that a catheter that has Candida or Bacillus or a coagulase-negative Staph, the actions may be quite different based on recognized outcome.

         Dr. Ohl's query about endocarditis; one of the hesitancies, the caution, about an indication for catheter-associated bacteremia or that the organism makes a huge difference and the recognition that particularly--not exclusively but particularly--with Staph aureus, the specter of endocarditis which is a segue to Dr. Patterson's comment of usually finding a source if the source is endocarditis but also grappling with the reality that I am sure will be more discussion today when there is Staphylococcal bacteremia, is the source endocarditis or is endocarditis a consequence, one of the many consequences, of the bacteremia regardless of what the initiating source was.

         So one gets into a chicken-egg phenomenon and the organism, the source, the relative role of removal, the kind of intervention, drainage, removal, extirpation in terms of valve replacement, that these things are incredibly complicated.

         Again, for starting points, as Dr. Sorbello said, I mean it is a very complicated history but it is a complicated topic and he has really captured the main points.  Some of these other things that have come up, it is not that they were ignored during the time but it is one of the reasons that the end conclusions were reached at the different points sequentially because, clearly, the patient population and the options have also evolved, I mean whether the patient is granulocytopenic and the chemotherapy and the kinds of catheters and the spectrum or organisms and the resistance mechanism--I mean, it is a very different world in 2004 from 1992.

         The last thing, very briefly, is I was not in second grade in 1965 like Janice Soreth.  On the other hand, I was not on the committee in 1965.  (Laughter.)

         DR. LEGGETT:  Tom and then John and then, unless there is anything really urgent, let's move on.

         DR. FLEMING:  Fred, back on your Slide 12, I had a follow-up question that was related to Jan's question.  Basically, on Slide 12 is you are referring to catheter-related BSI.  You have noted in that second-to-the-last point that we have got catheter-related bacteremia and bacteremia with unknown source.

         It is my understanding that your guidance document for CRBSI focuses exclusively on the former while, when we are going to go on this afternoon and talk about PBSA, will be inclusive to both.  Is that correct?

         DR. SORBELLO:  Yes, because there was discussion, actually, at the '98 Anti-Infective Drug Advisory Committee as to whether some proportion of the patients who have an unidentifiable focus but have catheters in place could actually have been catheter-related.  So there was a fair amount of discussion about that and how to really view them and how to consider them within the total spectrum.

         DR. LEGGETT:  John?

         DR. BRADLEY:  In stepping back for a moment and looking at some of the questions that Dr. Soreth had asked at the very beginning, in trying to get a protocol with inclusion and exclusion criteria that will work, the whole issue of the patient who has a fever and looks bacteremic is one that I think is an even more important issue than drilling down to how many blood cultures because that defines a small sub-segment of those who look bacteremic.

         Rule out sepsis is a very common admitting diagnosis in pediatrics, certainly, and probably in the adult world as well so, to me, one of the biggest hurdles is to try and figure out empiric therapy for bacteremic disease, suspect bacteremic disease, and then contrast that with how we are going to define the treatment, the drugs, the duration, for documented infection whether it be with the catheter in, with the catheter out, with endocarditis, without endocarditis.

         So the approach to empiric therapy, to the septic patient, I think, is a huge program and, in the April of 2004 hearing, the details of one of the pharmaceutical companies trying to study this, it is clear that we need to further define what empiric operational definitions we can use so that we can enrich for evaluable patients.

         The critical-care community with I.D. and pulmonary and surgical help made the first attempt to define SIRS and the septic patient.  They were unhappy with their definitions.  They are in the process of redefining them.  Three weeks ago in Boston, a group of us got together to try and redefine what is the septic patient because they all look septic.  You just don't know which ones are actually infected or not.

         As you had said, Jim, it is a moving target so those definitions from 1992 have been changed for adults.  We are changing them for kids.  We are not the only ones that want to study the septic patient.  There are biologics, pressers, all sorts of other people who are with us in trying to get our arms around what is this patient and what is the underlying process and how can we study it.

         DR. LEGGETT:  Celia?

         DR. MAXWELL:  Just one brief question on Slide 16.  While I know that a large sample-size requirement would be an issue, was there any speculation as to what kind of a sample size you would need to begin to answer the question?

         DR. SORBELLO:  An actual numerical sample size was not something that was directly discussed, but I think the core issue really regarding sample size is how do you define a catheter-related blood-stream infection, what criteria do you need to make that identification and, again, if you are dealing with a clinical study where there may not be uniformity in capturing catheter data because catheters are pulled and discarded without being cultured or there are not exit-site cultures done, et cetera, you are losing a major piece of information, at least microbiologic information, that is needed to properly do the study.

         So I think the size of the sample really dovetails with how you define it and what your criteria are to prove it, that it actually is a catheter-related blood-stream infection.  I think that tends to restrict the number of patients that can be enrolled because there are some rather strict microbiologic data that needs to be collected to do that.

         DR. LEGGETT:  Thank you, Dr. Sorbello.

         Janice, before we go on?

         DR. SORETH:  Just a quick comment to follow up on Celia's point.  I think we are going to hear more about this from the companies who are going to speak in the Open Public Hearing setting with regard to their experience with trying to do the trial, the number of patients screened versus the number of patients evaluable as it is, no pun intended, a sticking point for catheter-related blood-stream-infection trials.

         DR. LEGGETT:  We are now going to hear from Dr. Nambiar who is going to talk to us about the epidemiology of Staph aureus bacteremia.

Epidemiology of Staph aureus Bacteremia

         DR. NAMBIAR:  Thank you, Dr. Leggett and good morning everybody.

         (Slide.)

         In the next twenty minutes or so I will briefly discuss some salient epidemiology characteristics of Staph aureus bacteremia.  The clinical implications of this cumulative epidemiologic evidence as it relates to clinical-trial design will be discussed by Dr. John Powers in a subsequent presentation.

         (Slide.)

         Although staphylococci were first described about 125 years ago by Sir Alexander Ogston, it continues to evoke immense interest and respect among members of the medical community both because of its tendency to cause severe disease and its tendency to develop resistance to antimicrobials.

         (Slide.)

         Staph aureus is an important cause of bacteremia in hospitals both within and outside the United States.  Data from the SCOPE project from 1995 to 1998 showed that Staph aureus was the second-most common blood-stream isolate and it caused 16 percent of all hospital-acquired bacteremias.

         Data from pediatric institutions over a slightly longer time period showed that Staph aureus caused 9 percent of all hospital-acquired bacteremias.  In a seven-year study from a single institution in Switzerland which was an acute-care facility, it was noted that 14 percent of all bacteremias were caused by Staph aureus.

         Limited data is available on the incidence of community-acquired Staph aureus bacteremia.  In a study from four metropolitan areas in Connecticut in 1998, it was noted that the incidence of community-acquired Staph aureus bacteremia was about 17 per 100,000 persons.

         (Slide.)

         The increasing incident of Staph aureus bacteremia is paralleled by an increase in the incident of infective endocarditis due to Staph aureus.  About 25 to 40 percent of native value endocarditis is now caused by Staph aureus.  In a series of 329 patients with infective endocarditis from a tertiary-care facility, 40 percent of all endocarditis was caused by Staph aureus and the frequency of infective endocarditis due to Staph aureus increased from 10 percent in 1993 to 68 percent in 1999.

         (Slide.)

         Why is Staph aureus bacteremia different from other causes of bacteremia?  It can present with a wide spectrum of clinical manifestations ranging from uncomplicated bacteremia to severe fulminant and often fatal disease.  Complications are common and are often difficult to identify or to predict.

         Given its protein manifestations, it is difficult to standardize the extent of diagnostic procedures.  There is significant overlap of infective endocarditis and the two are often difficult to differentiate clinically.  Mortality from this disease remains high.  Additionally, it poses there issues both related to its development of resistance to common antimicrobials and uncertainty regarding the optimum length of therapy.

         (Slide.)

         The common risk factors identified for Staph aureus bacteremia include the use of intravascular catheters, hemodialysis, intravenous drug use and the presence of underlying illnesses such as diabetes mellitus and immunosuppression.

         (Slide.)

         Staph aureus bacteremia has been classified several different ways in the literature.  It can be classified as community- or hospital-acquired.  It is classified as primary or secondary depending on the absence or presence of an apparent primary focus of infection.  It is classified as complicated versus uncomplicated depending on the presence or absence of certain clinical characteristics.

         (Slide.)

         Although all patients with Staph aureus bacteremia necessarily have a focus of infection, it is not always apparent.  How often there is an obvious focus of infection depends upon the series of investigations performed, the presence or absence of an intravascular catheter, whether the population consisted primarily or intravenous drug uses versus non-drug uses, whether the disease was acquired in the community or in the hospital.

         On an average, there is no obvious focus of infection in about 20 percent of cases.

         (Slide.)

         This is a graph I have taken from a recent paper by Jensen describing the importance of focus identification in patients with Staph aureus bacteremia.  The line in red represents how often an unknown focus was reported.  This is data compiled from 14 published studies.  The line in blue depicts how often intravascular catheter was reported as the focus of infection.

         So, in the '90s, the two cross and the frequency of an unknown focus being reported has significantly decreased while that due to intravascular catheters is on the rise.

         (Slide.)

         In 1976, Nolan and Beaty reported in a retrospective study of 105 cases with Staph aureus bacteremia.  This is one of the earlier descriptions of two fairly distinct clinical populations, the first group consisting of 63 patients, all of whom had an apparent primary focus in infection.  These patients were more likely to have hospital-acquired disease.  They tended to be older with a mean age of 55 years.  They were more likely to have significant underlying illnesses.  Secondary foci were less likely and only two out of the 26 patients with infective endocarditis belonged to this group.

         In the second group of patients, none of them had an apparent primary focus of infection.  They were more likely to have community-acquired disease.  They were younger with a mean age of 37 years.  They were more likely to use intravenous drugs, more likely to have secondary foci and 24 out of the 26 cases of infective endocarditis belonged to this group.

         (Slide.)

         Subsequent studies have also documented that patients with community-acquired Staph aureus bacteremia are more likely to have an unknown portal of entry, more likely to develop metastatic disease and have a poorer prognosis.  All of these most likely reflect the fact that medical attention is sought later probably after the onset of bacteremia and before the institution of effective therapy.

         How often Staph aureus bacteremia is community-acquired differs between studies essentially because of differences in definition.  Most investigators would classify it to be community-acquired if a positive culture developed within 48 hours of admission to the hospital.  However, other investigators have used longer cutoffs of 72 to 96 hours.

         Using a 48-hour cutoff to define community-acquired disease, Jensen, et al., in their series of 278 cases of Staph aureus bacteremia from Denmark noted that just under 50 percent had community-acquired disease.

         Another important factor to consider in the definition of community-acquired Staph aureus bacteremia is if there was any prior contact with the healthcare system.  In the series by Morin, et al., from Connecticut that I referred to earlier, 192 patients had community-acquired disease and 62 percent of them had some prior healthcare contact.

         (Slide.)

         Staph aureus bacteremia is classified as complicated versus uncomplicated by different investigators using various definitions.  Some authors would classify it as complicated if a focus of infection was not identified or it was non-removable while others would classify complicated Staph aureus bacteremia if there was evidence of metastatic disease, deep-seated infections or other complications such as acute respiratory-distress syndrome, or DIC.

         In a series of 724 cases described from Duke University Medical Center, complicated Staph aureus bacteremia was defined as the presence of attributable mortality, evidence of infection extension or metastasis, embolic stroke or recurrent Staph aureus infection within the 12-week follow-up period.

         The authors noted the following four risk factors to predict the presence of complicated Staph aureus bacteremia; a positive blood culture at 48 to 98 hours later; community-acquired disease; skin findings such as petechia or vasculitis suggesting acute systemic infection; and persistent fever at 72 hours.

         (Slide.)

         We have already heard some discussion about Staph aureus bacteremia and catheters and, needless to say, it is very controversial.  Reports of increasing association of catheters and Staph aureus bacteremia pertain both to hospital-acquired and community-acquired disease and the increasing association with community-acquired disease may just be a reflection of changing medical practices.

         As with everything else I have presented so far, the definitions, really, vary between studies.  By and large, catheter is usually considered the focus of infection if there is no evidence of an alternate source and there is evidence of inflammation or infection at the catheter-insertion site or a catheter-tip culture is positive for Staph aureus.

         However, in the absence of catheter microbiologic data, either because the catheter was not removed or the catheter was not cultured, it is often a diagnosis of exclusion.

         (Slide.)

         Steinberg, et al. reported on the association between catheters and Staph aureus bacteremia over two time periods from Atlanta.  In the first time period, from 1980 to 1983, they noted that 25 percent of all hospital-acquired Staph aureus bacteremia were related to the use of intravascular devices.  There were no documented catheter-related community-acquired Staph aureus bacteremia during this time period.

         However, from 1990 to 1993, they noted that 56 percent of all hospital-acquired Staph aureus bacteremia and 22 percent of community-acquired Staph aureus bacteremia were associated with intravascular devices.

         In a larger series of patients, again from Duke University Medical Center, it was noted that about 50 percent of patients with Staph aureus bacteremia had an intravenous catheter as the focus of infection.

         (Slide.)

         The incidence of infective endocarditis in patients with Staph aureus bacteremia were really depending upon the patient population studied and the extent of evaluation performed.

         Traditionally, the following three bedside criteria, as proposed by Nolan and Beaty, in 1976 were used to predict to presence of infective endocarditis in patients with Staph aureus bacteremia, community-acquired disease, the absence of a primary focus of infection and evidence of metastatic disease.  However, subsequent studies have shown that infective endocarditis can occur in patients with hospital-acquired disease.  It can occur in patients who have an obvious primary focus of infection and can occur in a population of non-drug users.

         In a series of 59 patients with Staph aureus infective endocarditis, Fowler, et al., reported that 46 percent, in fact, had hospital-acquired disease.  In a series of 76 patients with Staph aureus bacteremia all of whom were non-I.V.-drug users 59 had an obvious portal of entry and 13 of these 59 patients had evidence of infective endocarditis.

         (Slide.)

         Infective endocarditis is often missed based on clinical findings alone.  In a ten-year study from Denmark, it was noted that endocarditis was missed clinically in over half of the 152 pathologically confirmed infective endocarditis due to Staph aureus.

         In a prospective series of 103 patients with Staph aureus bacteremia that was studied, 26 were noted to have infective endocarditis using the Duke criteria.  Clinical evidence was, however, seen in only seven patients, five of whom had peripheral emboli and two had new murmurs.  Transesophageal echocardiogram identified vegetations in 22 patients, abscess in two, perforation and new regurgitation in one each.

         (Slide.)

         Risk factors for Staph aureus infective endocarditis include the presence of native value disease which historically was associated with rheumatic heart disease.  However, structural abnormalities such as mitral-valve prolapse, degenerative disease such as aortic-valve sclerosis and congenital heart disease also predispose to development of infective endocarditis.

         Other risk factors include the presence of a prosthetic valve, history of intravenous drug use or prior infective endocarditis and community-acquired disease.

         (Slide.)

         How often patients with Staph aureus bacteremia will develop metastatic disease again varies between studies.  On average, about a third of patients will develop one or more metastatic foci.  In a retrospective study of 281 patients with Staph aureus bacteremia from Switzerland, 27 percent developed metastatic disease.  Common sites included the joints, kidneys, nervous system, skin and intervertebral disc.  Half the patients had more than one metastatic focus of infection.

         In a more recent prospective study of 68 patients published in 2000 by Ringberg, et al., and this was very appropriately titled "To Seek is to Find."  They noted that 53 percent of patients, in fact, had evidence of metastatic foci.  Patients underwent a fairly extensive evaluation including one or more of the following; X-rays, echocardiogram, bone or leukocyte scintigraphy.

         (Slide.)

         Risk factors for metastatic disease include community-acquired bacteremia, primary Staph aureus bacteremia, presence of prosthetic devices including orthopedic devices, implantable pacemakers and defibrillators.  The study also suggested that persistent bacteremia would be an important risk factor for developing metastatic disease.

         Among 104 patients with Staph aureus bacteremia, 59 percent of patients with a positive blood culture, more than 24 hours after starting effective therapy, developed metastatic disease compared to 17 percent without sustained bacteremia.

         (Slide.)

         The two important issues that come up in the discussion of metastatic disease is development of metastatic disease always represent lack of drug efficacy.  If not, from what time point after institution of effective therapy can we always attribute it to lack of drug efficacy.  And this will come up again in the discussion by Dr. Powers later this morning.

         There is some evidence in patients with infective endocarditis that suggests that once you institute effective therapy, the rate of embolic phenomenon seems to decline.  So, in a retrospective study of 207 patients with left-sided infective endocarditis, it was noted that the rate of embolic events decreased from 13 per 1000 patient days during the first week of therapy to less than 1.2 per thousand patient days after completion of the second week of therapy.

         However, in my review of the literature, I found there is only limited data available about inpatients with Staph aureus bacteremia regarding the time to development of metastatic disease.  In a small series of patients, of 39 patients with Staph aureus bacteremia, Libman, et al., reported that nine developed metastatic complications, one within the first week and eight after the first week of positive blood culture, two of whom developed metastatic disease four weeks after institution of therapy.

         (Slide.)

         This has already been brought up for discussion this morning; what is the optimum length of therapy.  It really depends on the extent of disease and the presence of host risk factors.  Generally complicated infections such as infective endocarditis and deep-tissue abscesses need prolonged duration of therapy somewhere in the range of four to six weeks.

         However, the appropriate length of therapy for patients with uncomplicated disease is still controversial.  Some investigators propose 14 days of therapy while others propose longer duration based on higher complication rates seen with shorter therapy.

         (Slide.)

         Acute systemic complications such as the acute respiratory distress syndrome, disseminated intravascular coagulation and septic shock usually occur within the first 48 hours.  Mortality in patients with Staph aureus bacteremia in the pre-antibiotic era was as high as 82 percent as reported by Skinner and Keefer in 1942.

         Currently, though, the mortality rates are much lower.  They still remain fairly high, between 16 to 35 percent.  Risk factors for morality include the severity of illness at onset of bacteremia, presence of an unknown source of infection, older age and noneradicable foci.

         About 12 to 15 percent of patients with Staph aureus bacteremia will develop recurrent disease.  Risk factors for recurrence include the presence of persistent bacteremia, a retained intravascular device and the presence of noneradicable foci.

         (Slide.)

         So, in summary, these are some of the important challenges we have identified with Staph aureus bacteremia most of which have a bearing on the design and conduct of clinical trials.  Clinically, it is classified several ways; community- versus hospital-acquired, primary versus secondary, complicated versus uncomplicated.  Due to its  overlap with infective endocarditis, there is often a need for echocardiographic evaluation.

         Because of its propensity to cause metastatic disease, there is often a need for extensive diagnostic procedures and as metastatic disease always due to drug effect is still unclear.  The association with intravascular catheters is sometimes based on stringent laboratory criteria but often is a diagnosis of exclusion.

         Treatment issues posed with Staph aureus bacteremia include the need to initiate empiric therapy given the nature of the disease, the choice of initial therapy which often is based upon the resistance patterns in any given institution and the uncertainty regarding the need for short versus long-course therapy.

         Thank you.

         DR. LEGGETT:  Thank you, Dr. Nambiar.

Questions from Committee

         DR. LEGGETT:  Does anyone have any questions?  Tom?

         DR. FLEMING:  I am trying to understand the sequelae for what might be, in fact, a PBSA cohort.  We have seen that there are several important clinical consequences that you have referred to that are mortality, endocarditis, metastatic disease.  And the evidence that you have shown, if I am understanding it, would suggest that effective antimicrobial therapies delivered sufficiently early in time could have an important benefit in reducing the metastatic-disease rates.

         Is that also true for the ability to reduce the rate of I.E. and mortality and would we be able to see those effects, particularly on mortality, by only following a moderate period of time because, as I understand from this, a lot of the mortality is, in fact, within 30 days.

         DR. NAMBIAR:  Even though there is some evidence to suggest that once you institute appropriate therapy, the likelihood or the risk of developing metastatic disease is decreased.  I think what is not clear at this point is is there a difference if metastatic focus manifests for the first time in the first week of illness, whether it manifests in the second week or in the fourth week, especially some metastatic foci like bone infections may not be evident early on.

         So what is not clear to us, and we are seeking help from the committee, is from what point on do we attribute it completely to lack of drug efficacy.  The other important issue that comes up is this drug that we are going to develop to treat Staph aureus bacteremia, should it have penetration to every potential site where Staph aureus can develop a focus of infection.

         DR. FLEMING:  Just to follow up on that, certainly some of these events are events that would have been seeded prior to the initiation of the antimicrobial therapy.  Some, however, presumably will be prevented which I would think would be a major benefit of such therapy.

         So, for infective endocarditis, is it reasonable to presume that we would be able, because of this chicken and egg--presumably some of this is, in fact, caused by Staph aureus bacteremia--is it plausible to think that, with effective therapy, we should be able to detect a reduction in the incidence cases post-therapy of I.E.?

         DR. NAMBIAR:  Yes, provided you have done everything to exclude I.E.

         DR. FLEMING:  Certainly, that would mean, and I follow you on that--that would reduce the diluting if we have done as much as we could to exclude cases that are already preexistent.

         DR. NAMBIAR:  I think, in my understanding, that would be a fair assumption.

         DR. LEGGETT:  Tom, there is the other problem of effective treatment and losing, nonetheless, because a good proportion of folks who have endocarditis lose their valve four to six weeks into therapy when cultures are sterile.  So that just further complicates that.

         Jan?

         DR. PATTERSON:  It was a nice review.  I just wanted to comment that since that Jensen review, there has been the emerging problem of community MRSA which has affected the rate of community Staph aureus in general.  Indeed, it does appear to be a different epidemiology in terms of the invasiveness of the infection and the fact that people may even stay bacteremic on bactericidal therapy for Staph aureus.

         So, probably, it is with the PBL talks that those particular strains have--that would probably be considered a risk factor, I think, for morbidity and mortality as well.

         DR. LEGGETT:  As well as an incentive for drug companies to produce new drugs.

         Joan?

         DR. HILTON:  It seems to me that, in trying to decide whether a therapy is effective, it would be great if there is time to evaluate a patient's baseline status, then treat, then evaluate the effective therapy.  I am wondering if there are patients in whom there is not time to evaluate that baseline status that it is imperative that you start therapy right away.

         If there might be a different group of patients in whom you actually can take a number of days or whatever time is needed prior to starting therapy, I think this leads into clinical-trial design.

         DR. NAMBIAR:  I think that would be an issue because I think, given the nature of the beast, I don't think we have the luxury of waiting for a few days before you actually initiate therapy.  In fact, you are more likely to have a situation where most patients would have received some empiric therapy, I think like the example Dr. Leggett said.  All that you would know is that there are Gram-positive cocci in clusters.

         If you all those risk factors, you are going to assume it is Staph aureus and, more than likely, I, as a clinician, wouldn't hold back treatment.  So I think having the luxury of waiting for some time and then evaluating the patient--and, again, the other issue that comes up is how much evaluation is good enough.  Do you subject every patient to every test that is known because this particular organism has a propensity to seed in multiple sites.

         So I think part of it is going to be a clinical judgment issue because I think it is hard to mandate that every patient be subjected to every radiologic procedure available to detect a potential occult focus.

         DR. LEGGETT:  Certainly expensive.  Joan, I think part of the problem is we are trying to get at a final common pathway, final common denominator, and there are multiple ways to go there.  So we oftentimes tell our residents to sit tight and don't start antibiotics until you know what is going on.

         But then there are the other people who are deathly ill that we start right away.

         Don?

         DR. PORETZ:  Just in answer to your question, also, there are significant medical-legal questions because I have reviewed multiple files and, if you suspect a bacteremia and you don't act on it, and a patient is bacteremic, the medical-legal repercussions are very, very significant.

         DR. LEGGETT:  As long as the outcome is bad.

         John?

         DR. BRADLEY:  I was going to mention, as Jan did, that, as we move forward, looking at PVL-positive community-acquired MRSA is going to be incredibly important because the disease is firmly within pediatrics right now and at the IDSA meetings a week or two ago, the warning was put out that children get it first and watch out, adults; you are next.

         The other issue that had to do with waiting to start antibiotics, it is the standard of care right now in a child who has fever to start antibiotics while your blood cultures are pending.  In order to go through a human research committee to present to a parent, mother or father, that we are withholding antibiotics and the potential complications is death I don't think would go over very well.

         DR. LEGGETT:  Chris?

         DR. OHL:  Just one other comment to add on that.  I think that we are also discovering that Staph aureus in its resistance has become somewhat heterogeneous.  More difficult to predict what and whom might respond to therapy that would thought to be sufficient based on microbiological MIC data.  We are still learning on this issue and it will be some time before that comes to fruition.

         DR. LEGGETT:  Thank you, Dr. Nambiar.  If there are no further questions, we will move on.

         Dr. Patrick Murray is now going to talk to us about Microbiological Considerations in Diagnosing Staph aureus Bacteremia.

         Dr. Murray?

Microbiological Considerations

in Diagnosing Staph aureus Bacteremia

         DR. MURRAY:  Thank you.

         (Slide.)

         John Powers asked me if I would give an overview of the microbiology of the issues that we are discussing today.  I notice we are running a few minutes overtime.  Hopefully, I won't exacerbate that problem.  I think that I would be able to cover this material within the allotted 20 minutes or so.

         (Slide.)

         What I am going to do is divide my presentation into three components.  I will start off with an overview of the blood-culture systems and I think the theme that I want to get across in that portion of the presentation is that not all negative cultures are created equally.  We tend to think that a negative culture means really there are no bacteria there.  I think what I can do, when I finish this presentation, is emphasize where, in fact, we can go wrong and miss the opportunity to detect organisms in the bloodstream.

         I will then talk a little bit about interpretation of the culture results and then, finally, the last maybe half of the presentation will be on identification of staphylococci, both the traditional methods for identifying the staphylococci as well as the newer genetic approaches to this.

         (Slide.)

         If we start off with an overview of blood-culture systems, the first thing that we have to do is collect an uncontaminated blood sample.  Skin antisepsis is pretty well defined, what should be done.  The surface to the skin should be cleaned with 70 percent alcohol.  It should be allowed to dry, air dry.  Then that is followed by either a 2 percent tincture of iodine, povidone iodine, or chlorhexadine.

         Of the three disinfectants that I just mentioned, the povidone iodine which is traditionally the disinfectant that has been used most commonly is probably the least effective and that is because it needs to be on the skin surface for about two minutes for it to kill the bacteremia that are there.

         2 percent tincture of iodine or chlorhexadine both work much faster and, for that sense, it is probably more effective at least based on traditional practices.

         The other question that could be raised is what is considered an acceptable rate of contaminated blood cultures.  I would say that there is no acceptable rate.  We don't want to have contaminated blood cultures.  But, generally, the goal of institutions is to keep the contamination rate below 3 percent.

         In my experience, what we find is that, although you may have a rate of less than 3 percent, in certain parts of the hospital, you may have much higher rates.  Emergency departments is a good example of that where the contamination rate can be much higher.

         I think in any sort of a program for reducing contaminated blood cultures, it is important for the institutions to know where their problems are and address those specifically.

         The volume of blood is the most important aspect of collecting a successful blood culture.  Most septic patients have less than 1 organism per milliliter of blood, whether that be bacteremia or fungi, that theme applies.  So the more blood you collect, the greater the chance of getting a positive blood culture.  There have been a number of studies that have looked at that.

         Those studies, then, form the foundation for the current recommendations that, for an adult patient between 20 to 30 milliliters of blood should be collected for each blood culture and that volume of blood is divided into two or three bottles. For children and for infants, there is proportionately less blood that would be collected.

         The dilution of blood in the broth is also important.  The minimum dilution is a 1 to 5 ratio between the blood to the broth that is in the culture systems.  Now, there are resin media that are available that allow you to have a more concentrated amount of blood in the broth.  I tend to think that that is not a good practice.  I think what we want to do is maximize the amount of growth medium that is available to support the growth of the organisms.

         The number and timing of cultures really depends on the type of--I am almost afraid to use the term bacteremia or septicemia right now, so I will use it in a more generic sense of bacteremia.  The number and timing is really dependent on the type of infection.  If it is a continuous infection, and that would be an intravascular infection like an infection localized on the heart valve or on a catheter, then, really, the timing is not critical because the bacteremia will always be present in the bloodstream.

         The key, then, is to collect enough blood to detect to organisms that are there.  On the other hand, if it is a localized focus, say, a lung or urinary tract or an abscess, then we would expect that, for many of those patients, you are going to have intermittent spillage of organisms into the blood and so the timing becomes critical and the number of cultures that are collected becomes critical.

         The recommendations are that two to three blood cultures should be collected within a 24-hour period of time.  Additional blood cultures really are not terribly useful unless you are looking for specific fastidious organisms.

         The methods that we use to culture bacteria and fungi in the blood have evolved over a number of years.  The manual methods, which consisted of bottles of nutrient media, really have been replaced by automated methods today.  I think there are very few laboratories that would have a manual method where they would inoculate the bottles and then periodically look at the bottles to see if there is evidence of microbial growth in those bottles.

         The lysis centrifugation system is a technique where you draw blood into a vacuum tube.  It has a lysine  reagent in the tube which lyses the blood cells.  You concentrate the organisms by centrifugation and then you take the pellet and you inoculate solid media with that.  The advantage of that system is that you can do a quantitative blood culture.

         The disadvantage is the lysine solution can lyse some organisms that you are interested in.  Staphylococcus pneumoniae is a good example of that.  In addition, there is a higher incidence of contamination of those cultures because of the manipulations.

         Most laboratories today use an automated method for processing blood cultures.  There are three major players on the market today in the United States.  Each of them are detecting growth or organisms by the metastatic activity of those organisms and that could be the production of carbon dioxide, the consumption of oxygen, and both of those can be detected by sensors or it could be detected by changes in pressure within the bottles.

         Those systems are comparable.  There are subtle differences between them, or among them.  I think each laboratory has their preference in what they would like to use but I would say all of those are superior to the manual methods that existed before.

         (Slide.)

         If we look at the interpretation of the culture results, the first is the time to detect the positive culture.  I could say that most positive cultures, probably 90 percent of more of the positive cultures that are detected in the laboratory are detected within the first 48 hours of incubation.  That is one of the advantages of the automated systems.  The manual systems took longer in order to detect a positive culture.

         Organisms like Staph aureus, the Enterobacteriaceae, betahemolytic streptococci, all of those will grow generally within the first 24 hours of incubation.  In contrast, organisms like the coagulase-negative staphylococci can take more than 24 hours on the average before you detect their growth.

         So one way of separating those organisms just within the laboratory is that if it grows quickly and it looks like a staphylococcus there is a greater chance that that is going to be Staph aureus compared with the other staphylococci.

         Cultures are routinely held in laboratories five to seven days.  There are some laboratories that hold bottles for a shorter period of time.  I think that does compromise their success in isolating some organisms, particularly on patients that have been started on antibiotics before the blood cultures were collected from those patients.

         Extension beyond seven days is generally unnecessary unless you are looking for more fastidious organisms such as those that may cause subacute bacterial endocarditis.

         The spectrum of organisms recovered blood cultures, this has been touched on already in one of the earlier presentations; about 10 to 15 percent of blood-culture bottles--blood cultures--are going to be positive, and they can be positive in one or both bottles that would be inoculated.

         The most common isolates are the coagulase-negative staphylococci, Staphylococcus aureus, Escherichia  coli, the Enterococci, Klebsiella and Streptococcus  pneumoniae and probably in that order, although that does vary from hospital to hospital depending on your patient population.

         The key point, though, is the most common organism that we will see in the laboratory will be the coagulase-negative staphylococci.  Most isolates of Staph aureus, Streptococcus pneumoniae, the beta-hemolytic streptococci, Enterococci, Enterobacteriaceae, Pseudomonas, the Gram-negative anaerobes and yeast are going to be significant.  So, if we see those in the blood culture, generally that is a significant finding.

         In contrast, most isolates of the coagulase-negative staphylococci, Corynebacterium, Propionibacterium and Bacillus are clinically insignificant.  Each of those are organisms that can colonize the skin surface and contaminate blood cultures.

         So the important point that I would make there is that the coagulase-negative staphylococci are the most common organisms we see and also are commonly insignificant.  In contrast, Staph aureus is the most common significant organism that we see but it is--again, we have to be able to differentiate that from the coagulase-negative staphylococci.

         The other point that I would make is that the coagulase-negative staphylococci do cause significant infections but almost always they are associated with either a contaminated line or another foreign body that is present in the patient such as the prosthetic heart valve, prosthetic joint and so forth.

         (Slide.)

         Identification of staphylococci has evolved over the years and I think, in the last three or four years, we are getting more sophisticated and I think, also, offer opportunities here to help with some of the issues that are under discussion today.

         What I would like to do, though, is to mention that, for blood cultures, the way we approach identifying organisms is different from how we do with other types of cultures.  Other cultures traditionally we are going to have the organisms isolated on a plate.  We can pick the colonies, set up the biochemical test and be able to identify the organisms.

         Because, in blood cultures, there are so few organisms in the patient's blood, we are forced to inoculate the blood into a large volume of broth and grow the organisms initially in that manner.  So what we are faced with, then, is a bottle with 50 to 100 milliters of broth and blood with the organisms present.

         Now, we can take those bottles.  We can subculture them and the next day pick isolated colonies and go ahead and do identification tests, but that is going to introduce a one-day delay.  So, traditionally, what most microbiology laboratories attempt to do are some rapid tests using procedures where we can concentrate the organisms from the broth and perform our test that way.

         Now, that subculture plate--traditionally, microbiologists will take a plate.  They will subculture the organisms onto the plate.  They put it into an incubator and they don't look at it until the next day.  In fact, if you go and you take that plate after four to six hours, you can see growth is present there, growth that you can use to set up your biochemical test and identify your organisms or set up your antimicrobial susceptibility test and have the results available the next day.

         Another approach would be to concentrate the organisms that are in the blood.  But, again, the first approach was to use differential centrifugation, a low-speed centrifugation, to remove the erythrocytes that are present and then a high-speed centrifugation to concentrate the organism.  You would take that pellet of organisms and use that to inoculate your test.

         A different approach to do that is to use the serum-separator, or clot tube, which are commercially available and you centrifuge your blood in that tube.  Your blood cells would be concentrated in the bottom of the tube.  The organisms, either bacteria or fungi, are concentrated on the top of the plug that is there and, above that, would be the rest of the blood.

         You can remove the organisms with a pipette and go ahead and set up your test from that.  Now, you can also take the broth, itself, and set up tests without concentrating the organisms.  The broth can be used for what I will talk about in a few minutes, the FISH test, or  fluorescent in situ hybridization test, can also possibly be used with molecular probes and I will discuss that also in a few minutes.

         But you need a heavier inoculum from a subculture plate or from a concentrated pellet of organisms to perform the coagulase test and the protein-A test.  The coagulase test is the ability of a staphylococcus to clot plasma, a very simple test.  It has been historically used to identify Staph aureus for many, many, many years.

         The recommended plasma that should be used is EDTA rabbit plasma, commercially available and readily available.  The coagulase enzyme--there are actually two enzymes that we are interested in.  One is bound to the surface of the bacteria and it is called, very originally, bound coagulase also referred to as clumping factor.  The other one is freely excreted by the bacteria.

         It makes a different which coagulase you are looking at.  For the bound coagulase, you can use a slide test or a commercial or latex agglutination test to detect the presence of that coagulase where the free coagulase is detected by a tube test.

         Now, let me explain what each of those tests are.  The slide test--what that means is you take your organisms from that pellet or from a plate.  You suspend it in a small drop of water and then you mix with that the plasma.  If Staph aureus is present, the organisms will clump together and it happens within about ten seconds.

         Another version of this test is commercial latex-agglutination test where, on latex particles, they have immobilized the antibodies to the bound coagulase as well as antibodies to protein-A which is specific for Staph aureus.  If the latex particles clump in the presence of the organism, then that is considered a definitive positive test for Staph aureus.

         The slide test is positive in about 85 percent of the isolates of Staph aureus.  That percent actually will fall if you don't have a heavy enough inoculum to be able to perform the test properly.  The latex test has a very good sensitivity and specificity.  It approaches 97 to 98 percent sensitive and specific.

         There are some organisms that will give you a false positive slide test.  I have listed them here on this slide.  There are also some organisms that will give you a false positive tube test.  The tube test is that you take a tube of about a half a milliliter of plasma.  You suspend your organism in that and you incubate it for four to 24 hours.

         Almost all Staph aureus isolates will be positive within four hours with that test.  Some, though, require extended incubation and you have to incubate them overnight before you can have a definitive negative test.

         What all this means for the coagulase test is that, if the slide test is positive, in general, you consider that definitive for Staph aureus and you report that.  If the slide test or latex test is negative, then you have to confirm that negative reaction with the tube test which would take four to 24 hours.  Again, the protein-A is just a variation of the latex agglutination test.

         (Slide.)

         Genetic probes for Staph aureus; GenProbe has developed the probe they market as AccuProbe that is used to identify Staph aureus.  It is a single-stranded DNA probe with a chemiluminescence label on it that is complementary to the ribosomal RNA in Staph aureus.  The advantage of targeting ribosomal RNA is there are about 10,000 copies of the RNA that is present so you have an inherent amplification of the test using this approach.

         The test inoculum is recommendedly prepared from a subcultured plate or, again, from that pellet of the broth.  It can be prepared from a broth culture.  The recommendation by the manufacturer is the turbidity has to be a McFarland 1 standard which is very heavy inoculum for practical purposes, much heavier than what you would see when a blood culture is initially detected as positive.

         The test time to perform this cell-lysis hybridization and detection is less than one hour.  So this would truly be considered a rapid test.  Marlow, last year, reported that the limit of detection with seeded blood cultures was approximately 10,000 colony-forming units per milliliter with this method.  That is at least 10-fold to 100-fold more sensitive than the limit of detection for the blood culture instruments.

         In other words, with a seeded study, it appears that you could use the blood culture broths directly to do this test.  I think additional tests have to be performed to confirm this but if this, in fact, is true, this would be an attractive alternative for identifying Staph aureus rapidly from a blood-culture broth.

         Still, the way that you can get around the possible problems of sensitivity here would be to pellet the organisms in a concentrate and use that to perform the test.  That should work very successfully.

         (Slide.)

         The last technique for identification of staphylococcus that I wanted to mention is fluorescent in situ hybridization or FISH test.  Applied Biosystems, which used to be called Boston Probes, developed a FISH test using synthetic peptide nucleic-acid probes that target, again, the messenger RNA of the specific bacteria, in this case, Staph aureus.

         They have a number of probes for different bacteria but the one that we are interested in today is the one for Staph aureus. The peptide nucleic-acid probe is a synthetic pseudopeptide that hybridizes complementary nucleic-acid targets.  Essentially, it is a synthetic peptide backbone with nucleic acids attached to it that would match up and be complementary to the nucleic-acid target.

         The probes have the advantage of a higher specificity and more rapid hybridization kinetics compared with traditional DNA or RNA probes.  In addition, the hybridization can be performed in a wide variation of salt concentrations which allows the speed in which this reaction can be performed.

         The probes also have a fluorescent label on them which allows detection by fluorescent microscopy.

         (Slide.)

         I apologize for this picture.  This wasn't really what I wanted to show you.  What I wanted to show you is what is here in this lower right-hand corner but I am not sophisticated enough with computer to figure out how to cut that little picture out and show that alone.

         So this is from one of Boston Probe's research articles that were published.  It showed a series of different organisms.  There was an E. coli.  Salmonella is No. 2.  No. 3 was Pseudomonas auruginosa and No. 4 was Staph aureus.

         The first two columns going down showed auto-fluorescence.  The next four columns, they used specific probes.  So, under C, it was the specific probe that was for the E. coli and only the E. coli is fluorescing.  The second one was for Salmonella.  The third one was for Pseudomonas and the last one, in the lower corner here, was the specific probe for Staph aureus.

         Truly, that is what it looks like when you perform these tests.  They really do jump out at you.  The organisms can auto-fluoresce and they have corrected with special filters for the auto-fluorescence.  So it really is a fairly nice, in my experience, and we have used this now for about three months; it is a system that works fairly nicely.

         The downside of this is the total test time is approximately two-and-a-half hours.  It is not a problem if your blood cultures are detected early in the day but if it is detected late in the day and, because of the, I think, relative sophistication of the interpretation of the reaction, it is not a test that can be performed off-hours.           There have been three studies using these probes; specifically, the Staph aureus probe with positive blood-culture broths and the sensitivity and specificity for each of the studies was 100 percent.  So it appears that this is a very sensitive and specific reaction when used with blood-culture broths.

         I think that was my last slide.

         DR. LEGGETT:  Thank you, Dr. Murray.

Questions from Committee

         DR. LEGGETT:  Are there any questions?  Don?

         DR. PORETZ:  Through the years, it is obvious that we are seeing more and more blood cultures being reported back as coagulase-negative Staph.  Not all those patients have lines in place.  Do you think it is because of the way the blood is collected?  Do you think it is because what is happening in the laboratory?  Why are we seeing so much coagulase-negative Staph in blood cultures?

         DR. MURRAY:  I could probably make one comment about the laboratories.  In my opinion, one of the advantages for the new blood-culture systems is they are noninvasive systems.  Once you have inoculated the blood into those, you don't go back into those bottles where traditionally, either with manual systems or with the early automated systems, there are multiple entries into the bottles. So it is most likely the collection problems.

         DR. PORETZ:  I get the impression, after watching our laboratory technicians draw blood, at least in my hospital, they are not as careful as they were several--they are being--you know, it is a matter of dollars and cents.  They speed these people up from person to person.  I think that is probably the major reason and we are getting what we are paying for.  We are, therefore, treating more patients than we need to treat, unfortunately.

         DR. MURRAY:  Very clearly, and there have been, I think, excellent studies that have looked at this, if you have a dedicated phlebotomy team that collects blood cultures, you get much better results.  If you have technicians that have other responsibilities, if you have nurses that have other responsibilities, you have medical house staff that are doing a lot of different things, they are not trained well and they don't take the time to do it properly.

         Again, my experience is if you look at where you have problems, you can usually identify key areas.  That is really where the laboratories need to focus their attention in getting the proper cultures collected.

         DR. LEGGETT:  John?

         DR. BRADLEY:  It is wonderful to see the progress in molecular techniques in increasing how quickly we can identify organisms once they have come out of culture.  However, at the bedside, for enrollment in a study, what we would really like is a test, a molecular test, we can do on plasma of the sick patient so that, within two-and-a-half hours of entering the hospital, we would have something to let us know whether they are infected or not.  Can you comment on progress in that direction?

         DR. MURRAY:  I think that the difficulty that, if you look from the microbiology perspective, the difficulty that you are working with is there are very small numbers of organisms present in the blood and that you have to amplify that.  Not every company that makes molecular probes has targeted blood cultures as the place to go because, if you come up with a successful system, it is wonderful because there are a lot of people that would want to run those tests.

         I am not optimistic about that, but possibly that will happen.  Other approaches would be to look at a patient's response to the organisms, and so you look at cytokine profiles.  There is a lot of work that is being done with that as well.  And that is part of problem.  It is not specific.

         DR. LEGGETT:  Barth?

         DR. RELLER:  I would like to add three more reasons, Don, why there are more positives.  One is where the blood is collected from.  There are more and more catheter draws because it is convenient.  Two is time is money, and the speed.  If one uses povidone iodine, as Pat pointed out, it takes time so that you have--and the Gram-positives are the hardest ones to kill or to disinfect.

         The third thing that is, I think, unequivocal and has been shown in controlled clinical trials is the newer instruments including media for institutions that use charcoal and resin-containing bottles.  They are more sensitive.  But they are also more sensitive at picking up that solitary coagulase-negative staphylococcus that is derived from the first two issues.

         So there is a tradeoff.  You get more reals but you unequivocally get more contaminants.  I would reinforce Pat's assessment of John's query about PCR.  PCR, or nucleic amplification, is fantastic for some entities where the number of targets is large; acute HIV infection, hepatitis C, HSV, et cetera.  Pat emphasized it is unequivocally true, many, and shown by Washington, Murray, others, at least half, more than half, of real staphylococcal bacteremias were less than one organism per ml, so that one would have a large volume.

         There are currently not yet processes in place, not that it couldn't be developed, that one could extract the 20 to 30 mls of blood, because if you don't have a target, you don't have a positive nucleic acid.

         DR. LEGGETT:  Dr. Murray, a question.  On your slide about interpretation of culture results, it stated that Staph aureus is detected in less than 24 hours and other Staph greater than 24 hours.  Are you implying less inoculum or slower growth?

         DR. MURRAY:  It probably is not the inoculum effect.  It is probably more related to the rate of growth of the organisms.  If you just look at colonies of Staph aureus and colonies of coagulase-negative Staph on a plate, generally the Staph aureus is a much larger organism, the colonies.  So it is growing faster.

         The inoculum is an important issue though because the time to detection is influenced by the number of bacteria that are present.  One way of assessing whether a catheter is the source of a positive culture, or a septic patient, is to look at how fast the organisms--how fast the cultures collected from a catheter group compared with cultures collected at the same time from a peripheral vein.

         DR. LEGGETT:  Any further questions?  Thank you, Dr. Murray.

         Do we want to take a fifteen-minute break now?  I think so.  I was chided by one of the speakers last time because I wasn't accounting for older bladders.  So it is now 10:15.  Let's come back at 10:30 for the Open Public Hearing.

         (Break.)

Open Public Hearing--Extra Session

         DR. LEGGETT:  This will begin our extra session of an Open Public Hearing which was not on the Federal Register Announcement.

         Before we have Dr. Tally speak to us, I would like to make the following announcement.  Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making.  To insure such transparency at the Open Public Hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation.  For this reason, FDA encourages you, the Open Public Hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.

         For example, the financial information may include a company's or group's payment of your travel, lodging or other expenses in connection with your attendance at the meeting.  Likewise, FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships.

         If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

         Dr. Tally?

         DR. TALLY:  In the spirit of what Jim just said, I am the Chief Scientific Officer of Cubist and I am a stockholder of Cubist.

         (Slide.)

         I would like to thank the agency for inviting Cubist to present at this important advisory committee meeting.  We are currently in trial in a study of Staphylococcus aureus bacteremia endocarditis.  I would like to present some of the experience we have had with this particular study.

         I will give you the summary up front using the old teacher attitude of I am going to tell you what I am going to tell you, tell you, and then review it at the end.

         (Slide.)

         Staphylococcus aureus bacteremia, as we have heard from the previous speakers, is a significant unmet medical need.  It is a heterogenous population which includes endocarditis and in these heterogeneous populations, there are different outcomes.  There is a lack of a placebo effect with Staphylococcus aureus bacteremia and I will address that during this talk.

         It is a difficult study to do, a bacteremia endocarditis study, but it is possible and we will look at that today.  However, when we look at this, traditional noninferiority assessment may not be best or the only association of efficacy in this seriously ill group of patients.

         (Slide.)

         What is the high unmet medical need?  We have heard, from the earlier speakers, that Staph aureus is a leading cause of bacteremia.  It is a virulent organism.  Indeed, it is one of the premier pathogens to infect man.  It was discouraged in the preantibiotic era.  It leads to endocarditis, metastatic infections and/or death.

         As we have heard this morning, Staphylococcus aureus bacteremia is both a cause and a result of endocarditis.  Finally, there is changing epidemiology, as we have heard today and, in that changing epidemiology, it is a therapeutic challenge and that is compounded by the increasing resistance to beta-lactam drugs and the increasing tolerance to vancomycin.

         (Slide.)

         What is the mortality and what is the frequency of Staph aureus bacteremia?  This is data just published in August from the SCOPE study looking at 20,000 isolates of nosocomial bacteremia published in CID.  When you look at coag-negative Staph, it is 31 percent of the isolates, the coag-negative Staph, with a crude mortality of 21 percent.

         With Staph aureus, incidence of the 1999 survey, SCOPE survey, was 16 percent in 2004.  It has jumped to 20 percent of the isolates.  So Staph aureus as a cause of nosocomial bacteremia is increasing.  The intended mortality, the crude mortality, with Staph aureus, in this particular study was 25 percent.

         (Slide.)

         What about the placebo effect.  This is data that was mentioned earlier.  The Skinner study published in the Archives of Internal Medicine in 1941 looked at the outcome in patients with Staph aureus bacteremia and the case-fatality ratio was 82 percent.  You will notice if you are 50 or older, which most of us are in the room, the mortality goes up to almost 100 percent.

         With this, when you look at Staph aureus endocarditis non-treated, it is 100 percent fatal as are other endocarditises in the preantibiotic era.  So the placebo effect in Staph aureus bacteremia or endocarditis is little or none.

         (Slide.)

         The next confounder in Staph aureus bacteremia is whether the patient has a MSSA bacteremia or an MRSA bacteremia.  This is a slide from Sarah Cosgrove's meta-analysis looking at that.  If you look at mortality with MSSA, it is 23.4 percent.  With MRSA it is 36.4 percent.  She controlled for confounding variables in clinical backgrounds.  So there is a consistent finding that mortality is increased when you have MRSA causing the infection.

         (Slide.)

         When you do have MRSA, the main therapeutic modality has been vancomycin.  The problem emerging from vancomycin has been the emerging resistance.  We saw VRE outbreaks in Europe in '86.  It continues to today.  VISA was first reported from Japan in 1996.  We still see it albeit it is very low.  Heteroresistance in vanco was noticed by the CDC in 2001 and it continues to be a rising problem.

         More recently, we have had vancomycin-resistant Staphylococcus aureus albeit there are only three isolates known at this time.

         (Slide.)

         When you do look at vancomycin in this particular area of therapy for MSSA and MRSA, two things come out.  One, Chang, in an analysis of over 500 cases of bacteremia, looked at MSSA, whether it was treated with vancomycin or nafcillin.  In that study the conclusion was that nafcillin was superior to vanco in the treatment of MSSA bacteremia and why most people recommend switching off vanco to nafcillin when you have nafcillin-susceptible.

         More recently, there has been disturbing data with these heteroresistent strains and vancomycin has been known to fail in MRSA bacteremia back into the early 90s in studies coming from San Francisco.

         The heteroresistance and tolerance problem probably is the most common problem we are seeing now and it has increased and heteroresistance is noted to be associated with increased failures.

         The most recent paper in JCM in June of this year looked at a biased sample of failure patients, looking specifically at the MIC of the organisms to vanco, came up with a surprising result.  By NCCL criteria, an isolate with an MIC or 4 or less to vancomycin is considered susceptible.  However, when the group at the Deaconess looked at 30 isolates, it had some rather disturbing outcome when you broke up the isolates based upon the MIC.

         Those isolates with an MIC of 0.5 or less, there was a successful outcome in this group of 55 percent.  The overall group of 30 patients, it was a 23 percent favorable outcome.  However, if the isolate had an MIC of 1 to 2, the favorable outcome was 9.5 percent and that is approaching what we saw with the placebo effect that Keefer published in 1941.

         So one has to look at vancomycin in this group of patients and particularly wonder about these ones with MICs of 1 to 2.

         (Slide.)

         So, with that background, when we were looking at our drug, daptomycin, and how to guide physicians in treating, and, particularly, what we were asked is how do we treat bacteremia, we made the decision back in 1999 to look at patients with bacteremia and endocarditis because, at that time, endocarditis is a registerable indication according to FDA guidelines.

         In consultation with the FDA, we undertook at study of daptomycin and infective endocarditis and bacteremia to specifically Staph aureus.  The criteria to get into the study is you had to have a positive blood culture for Staph aureus.  It is multicenter, both in the U.S. and Western Europe.  It was randomized.  But, because of safety concerns, it was an open-label study which adds complexity that I will talk about in a minute.

         We did add a blinded external adjudication committee.  It is a comparative control and it was nafcillin versus vancomycin.  In the beginning, we just treated bacteremia and right-sided endocarditis.  There was an amendment of the protocol in April of 2004 to include a left-sided endocarditis.

         (Slide.)

         What were the challenges in this study?  You have heard this morning that Staphylococcus aureus bacteremia is a heterogeneous group of patients.  We use the modified Duke criteria to try and give some semblance of what type of patient we had at admission criteria.  This is the phenomenon.  The clinician is confronted with a positive Staph aureus blood culture and you don't know which group they are going to fall into.  You only determine that during the course of therapy with many diagnostic tests.

         What we did is we classified our patients by the Duke criteria into definite or possible or not infective endocarditis.  Part of that was a centralized reading of our echos, not leaving it to the original site.  Finally, at the end, there will be an overall determination of responses in each subgroup; that is left-sided endocarditis, right-sided endocarditis and bacteremia.

         This is a difficult study to enroll and I will show you the magnitude in the next couple of slides.

         (Slide.)

         So what we did is enrolled numerous sites.  There were some ethical considerations and that was you are treating patients with a high mortality if they have endocarditis.  So the treating physician has to know.  We looked at that open-label design.  We also put in place a safety data-monitoring committee to make sure there was not a safety issue in the ongoing study.

         What about the bias due to an open-label design?  We addressed that somewhat with the blinded independent external adjudication committee.  It is composed of ID experts that are experts in infective endocarditis.  They will determine diagnosis and outcome.

         Finally, with the type of study here, we have heard about relapse, you need long-term follow ups.  So the test of cure is actually out at six weeks and a post-study visit is actually out three months.  So the length of the study is rather long.

         There are extensive inclusion and exclusion criteria which affect the conduct of the study and it is related to the drugs used and the patients being enrolled.

         (Slide.)

         How did we make out in this study?  When we looked at our diagnosis, and we are over 200 patients which is what are target was, and we looked at, by the Duke criteria, at these patients, about a third of them did not have IE based upon the Duke criteria and would consider those having bacteremia.

         We had a large group that were possible IE.  They met the Duke criteria but they did not have a positive echo.  Finally, we also had a smaller group that had definite infective endocarditis.  It is proven by echocardiography.

         (Slide.)

         How many patients did we have to screen to get this over 200 patients?  We screened over 5,000 patients to get this over a two-and-a-half-year period.  But it is doable.  And we are, at this point--right now, we are in discussions with the FDA on going forward with this particular study.

         (Slide.)

         So I am back to the summary from the beginning.  There is a significant unmet medical need.  I think it has been brought out time and again this morning.  The heterogeneous population includes patients with endocarditis and these heterogeneous populations all have different outcomes.  So you are going to have to do some type of subanalysis of those groups.

         There is a lack of a placebo effect in this so it raises some questions we will get to.  It is a difficult study to do, expensive, but it is possible to do these studies as we have shown.

         Finally, traditional noninferiority assessment may not be best in this serious illness or the only assessment of efficacy and I would throw that open for discussion at the end.

         Thank you.

         DR. LEGGETT:  Thank you, Frank.  We will take some questions.  Alan?

         DR. CROSS:  When you said that you screened over 5,000 patients, was that 5,000 patients with positive blood cultures or with Gram-positive positive blood cultures?

         DR. TALLY:  It was 5,000 patients with positive blood cultures.

         DR. LEGGETT:  Jan?

         DR. PATTERSON:  I was wondering on that Sakoulas JCM 2004 study, the vancomycin--we know that physicians tend to underdose vancomycin.  I was wondering, did they use a 10 milligram per kilogram dose and/or were there any trough levels measured?

         DR. TALLY:  There were trough levels and they were, I think, above 15.  So they took that into consideration with these.

         DR. LEGGETT:  Frank, could you elaborate a little bit about the exclusion--was it mostly the inclusion-exclusion criteria that you had the 5,000 but only 200 enrolled?

         DR. TALLY:  I have my Dave Letterman list of ten reasons.  The biggest reason, in our study, turns out to be creatinine clearances below 30.  Our drug is cleared by the kidney.  We didn't have guidance in that area so it was a major exclusion criteria in this.  And, indeed, that is something we are working on now to try and include patients in the future with ongoing studies of patients with renal failure being evaluated with a specific dosing regime.

         It was not the only reason.  That was a primary reason and, in those patients, they probably had other reasons for being excluded also.  But, also, there were a whole bunch of other reasons.  One, they were already on the drug for greater than 48 hours, it was effective.  Two, you couldn't get the consent in this serious illness.  Three, there was renal failure.  Four, they were in imminent threat of death so we didn't want to put morbid patients in.  Fourth--let me pull out my sheet, my cheat-sheet for that.

         A large group where they intravascular material that couldn't be removed were excluded.  Severe neutropenia.  Elevated bilirubins above 3.  So there were a number of these criteria to try and focus on the disease and get it.  We are not giving out the exact numbers on that.  We have submitted all of that data to the FDA.  We will be discussing that and it will come out sometime when we complete the study.

         DR. LEGGETT:  Tom?

         DR. FLEMING:  Could you clarify your last point?  It is somewhat vague.  You haven't gone into any details about what type of noninferiority assessment was planned.

         DR. TALLY:  Excuse me?

         DR. FLEMING:  Could you clarify your last point about the noninferiority assessment.

         DR. TALLY:  Not being a statistician, I can't.  I don't know what type of analysis should be done and that would be something we should talk about.  But I think with the number of patients that you have to enroll, you would have to screen, to enroll just 200 patients.  And then you have to do a subset.  If you want to look at the subset analysis of the different groups of patients within here.  It is going to make it an impossible study to do if we are doing a noninferiority study.

         So one would like to know if there are alternate ways to study this group of patients that, one, do not have a placebo effect; two, have a definite endpoint of you either clear the bacteremia or you don't.  Third, to take into those the effect of not being able to do a study to assess all of these subgroups.

         So I, personally, don't know what type of analysis should be done and would throw that out.

         DR. FLEMING:  Just to lay out the principles here, though, the analysis that you would do should allow you to conclude that you have an efficacious intervention.

         DR. TALLY:  Correct.

         DR. FLEMING:  And in a setting that you are referring to here as--you are calling it lack of a placebo effect.  I think what you are saying is a setting where you are going to have very few favorable outcomes in the absence of effective therapy.

         DR. TALLY:  Correct.

         DR. FLEMING:  But where there are effective therapies then a critical question is to ensure that an intervention isn't clinically meaningfully worse than what, in fact, you could achieve with existing therapies which also is, in fact, addressable through a noninferiority paradigm.

         DR. TALLY:  I think you hit on it.  It is the clinical evaluation of it and that is what we are in discussion with the FDA right now.

         DR. FLEMING:  Celia?

         DR. MAXWELL:  On your Slide 12, on the diagnosis of enrolled patients by the modified Duke criteria at baseline, I had a question--two questions, actually, of the definitive and the possible infective endocarditis, what was that in actual numbers and also, of these two populations, were any or what percentage of them in each of these categories were shown to have vegetations, let's say, on echo.

         DR. TALLY:  The definites had echo evidence of vegetation.

         DR. MAXWELL:  All of them.  And what number was that?

         DR. TALLY:  Oh; we are not giving out the numbers at this point in time.

         DR. MAXWELL:  Okay.

         DR. TALLY:  Because the numbers are not complete.  We are on an ongoing study where there are a number of patients where we haven't determined--they are under analysis.  So I am constrained from giving out numbers because, in addition to being regulated by the FDA, I am also regulated by the SEC.  And I don't want to give out any misleading information.

         DR. LEGGETT:  Don?

         DR. PORETZ:  Frank, do you anticipate, if this drug is of value and is approved, is one going to be, when they are treating infective endocarditis, obligated to get serum levels of the drug?

         DR. TALLY:  Since I haven't seen the data and the study is still ongoing, I think we have to wait to draw that conclusion.  We had built into the study a pharmacokinetic study on all patients that we will be able to use when we look at the outcomes when the study is closed down and the blind is broken.

         DR. LEGGETT:  Barth?

         DR. RELLER:  I just wanted to comment that, at first, it seems the 200 out of 5,000 is a small number.  But it is exactly what one would expect given the physiologic exclusions.  I base that on the largest review published in the '90's on bacteremia; exactly 9 percent of all positive blood cultures grew Staph aureus assessed by an infectious-disease clinician to be true, which were almost all of the Staph aureus.

         What it is telling you is that half of all blood cultures obtained in tertiary-care hospitals in the United States are contaminants or unknown.  So you do the numbers and, if you took 1,000 reals relative the positive, same institution, it is 9 percent.  So basically it is capturing half of the ones who really have it.

         DR. LEGGETT:  Yes.

         DR. FETZER:  (Inaudible comments.)

         DR. LEGGETT:  Could I ask you to speak into the microphone, please, and identify yourself.

         DR. FETZER:  Olaf Fetzer, senior vice president, Cubist Pharmaceuticals, responsible for R&D.  I just wanted to mention to Frank, as a correction; of the 5,000 screened, these were all Staph aureus confirmed.

         DR. RELLER:  It wouldn't make it much different if it were all staphylococci in coming down to--but then there are other reasons why people chose not to enter someone into the trial apart from the exclusion criteria mentioned.

         DR. TALLY:  In response to Bob's question, one, and to clarify, the only patients that were screened has positive Staph aureus cultures.  So that has been eliminated right away.  There are a whole list--there are about 30 reasons why patients didn't get into the study.  I gave you some of the top ones and I don't have the full list right with me.

         If somebody drops out for one of the higher reasons, it doesn't mean they have a lower reason for exclusion.  What it is saying is that this--and it is a very sick patient population--when you build in your exclusion and inclusion criteria, it eliminates a lot of patients.  It is just getting that proper window where they haven't had other therapies and getting a patient to consent to your study and to get the physician to take out devices is problematic in this group of patients.

         DR. RELLER:  I was just running the numbers based on the earlier question and on the comment that it was all positive cultures, not all cultures obtained.  If one did all positive cultures, you could count on, at most, 9 percent.

         DR. LEGGETT:  Thank you.  Let's move on.  Thank you, Frank.

         Our next speaker is Dr. Powers who is going to talk to us about clinical-trials issues with studies of Staphylococcus aureus bacteremia which will be followed, again, by questions from the committee.

Clinical Trials Issues with Studies

of Staph aureus Bacteremia

         DR. POWERS:  Thanks, Dr. Leggett.

         (Slide.)

         I think that is a good introduction because what Dr. Tally brought up--

         DR. LEGGETT:  Excuse me, John.  I have to close the Open Session.

         DR. POWERS:  Oh; go ahead.

         DR. LEGGETT:  The open session is closed.

         DR. POWERS:  That took care of that.  What Dr. Tally brought up was that it was very hard to evaluate the endocarditis subset within the group of people with Staph aureus bacteremia.  But what they did find was 5,000 people with Staph aureus bacteremia.

         So what I would like to talk about today is can we define a new indication of primary bacteremia due to Staphylococcus aureus and then maybe look at subsets within that to try to evaluate those patients.

         (Slide.)

         So the first thing we are going to talk about is actually defining this indication and ask the committee whether they think that this is a worthwhile indication for people to pursue and does it actually add some information for clinicians.

         Then we would talk about the place of this potential indication in a clinical-development program and what kinds of preclinical and prior clinical-trials work would be helpful in evaluating a drug that would be potentially helpful in this disease and then, finally, go through some of the issues in designing and analyzing clinical trials of this potential indication.

         We will go through some of those issues of selecting the appropriate patient population to study, talk about how would we evaluate endpoints with what Dr. Nambiar brought up about how would one evaluate metastatic disease that may occur on treatment, talk about this issue of selection of duration of therapy, the issue with controlled drugs--and we will go into a little bit about this dictum of vancomycin and nafcillin and how they compare to each other, and then some of the statistical considerations including the question Dr. Fleming asked about noninferiority.

         (Slide.)

         So the first question we would like the committee to ask here, and I am going to do this talk in terms of questions and then put some of the pertinent information underneath it.  So, should primary bacteremia due to Staph aureus constitute a separate indication?

         Before we answer that, we actually have to say what is an indication.  Well, an indication and the patients actually studied should be something that we can clearly define.  That is for two reasons.  One, obviously, we need to be giving some information to clinicians about how they appropriately select patients for treatment with that drug once it is determined to be safe and effective.  Also, we need to be able to write that into prescription product labeling so that people can understand who was studied and where the drugs should be used.

         So what we are suggesting is that maybe one definition of primary bacteremia due to Staph aureus, and this gets back to what Dr. Patterson asked, we are not defining in the same way as it was defined in some previous trials.  What we saw was that it is variously defined depending upon how you look at it.

         So our suggestion here would be that it is evidence of systemic signs and symptoms with positive blood cultures for Staph aureus and no other identified source of infection at the time of enrollment.  The reason why we brought up signs and symptoms is something that Dr. Reller just brought up, that maybe as much as 50 percent of positive blood cultures don't represent real disease.

         What the committee had discussed in the past, in 1998 and 1999, was that bacteremia alone is not an illness.  We need to link that to some signs and symptoms that the patient actually has.

         It shouldn't be that hard because, usually, clinicians draw a blood culture when the person is having some systemic signs and symptoms.  So then the question comes up is should one differentiate from secondary bacteremias--that is, patients who have a known source of infection such as pneumonia, complicated skin infections, et cetera.

         What the committee had told us back in 1999 was they were concerned that there may be differential efficacy of drugs based on the site of infection.  We have certainly seen recent drugs that were effective in, say, complicated skin but did not look effective in other body sites like pneumonia.  So, depending upon where the patient's original site of infection is may be important in determining drug efficacy.

         Also, bacteremia related to an intravascular catheter--when we looked through a lot of this literature--is often really a diagnosis of exclusion.  Sometimes it is based on a positive catheter tip but, again, when we went back to the 1970s and tried to evaluate where does that information come from on positive catheter tips, again, there really is no gold standard to say what were those things compared to to determine that a positive catheter tip actually implied that the person had a true catheter-related infection.

         So the question came up, since it is often a diagnosis of exclusion and what we have heard from people in industry that we will go over this afternoon is that it is very often difficult to get that piece of information from the catheter because it has often been discarded by the time you get around to the patient.

         So could we devise an indication where intravascular-catheter-related infections were subsumed under this primary bacteremia indication.  But, really, the question is would this indication provide useful information to clinicians.  If we already know that a drug is effective in Staphylococcus aureus infections with a primary source of infection, would this provide this some additional data to knowing that the drug is effective in pneumonia, complicated skin, et cetera.

         That brings up something Dr. Tally just talked about.  Would this indication provide us the opportunity to study patients that would not be included in those with a primary source of infection.  Namely patients with endocarditis would be the big issue there.

         (Slide.)

         In fact, it is such an important issue that does efficacy in primary bacteremia due to Staph aureus imply that the drug is effective in endocarditis.  Clinically, what we always worry about when you see a person with a Staph aureus in their bloodstream, especially if they don't have an identified initial focus of infection, is they may have an occult case of endocarditis.

         So why is that important in terms of a clinical trial as well as clinically?  Because, first of all, it implies different outcomes in the patient and, in fact, Dr. Tally referred to a paper by Chang in Medicine.  There is another paper by the same authors in that same journal that looked at risk factors for outcome in people with Staph aureus bacteremia, 31 percent mortality in the people who had endocarditis versus 20 percent in the people who didn't.  So big difference in outcome if you have endocarditis or not.

         It also may imply a different duration of therapy as well, and that remains controversial; two weeks, four weeks, six weeks, what would be the appropriate duration in these people.

         So then the question comes up is can these drugs be studied without examining efficacy in endocarditis and, even within endocarditis, are there differences between right- and left-sided disease.  So one of the things we would like to ask the committee is can these drugs be studied in a staged approach of first studying uncomplicated Staph aureus bacteremia or at least people unlikely to have a complication; then study right-sided endocarditis; then study left-sided disease.

         In addition, how would we approach drugs that may not demonstrate some potential efficacy for endocarditis based on either in vitro or animal testing but still may be effective in patients who have a primary source without endocarditis.

         (Slide.)

         So the next question that comes up is where would these kinds of studies fit in the overall clinical-development plan for a new drug.  We brought these issues up in April of 2004 at a public workshop co-sponsored by FDA, the Infectious Disease Society of America and the International Society for Antimicrobial Pharmacologists.

         Some of the participants, when we brought this up, a little to our surprise, were very hesitant about going forward with studying drugs without some prior information that the drug may be effective given the serious nature of this disease and the potential for development of endocarditis.

         (Slide.)

         One of the things that the folks at that meeting suggested was that there should be some data from trials in this indication and that this kind of indication probably would not be the sole basis for approval.  In other words, if a new drug came forward and this is the only thing they wanted to study, that that might be problematic and that we would probably look at this in terms of the overall efficacy of a drug in treating serious Staph aureus infections.

         So, again, they expressed this view of that we needed some more infection.  So then the obvious question is what kinds of information would be helpful prior to studying a drug in a serious disease like this.

         (Slide.)

         The first question is what kinds of preclinical studies would be helpful in forming these hypotheses about potential efficacy and safety in this indication.  And that would include both in vitro data and animal models.  The in vitro data would consist of looking at the biological activity against isolates of Staph aureus and that brings up another interesting question about what is the clinical significance of bacteriostatic versus bactericidal drug.

         Dr. Pankey and colleagues wrote a very interesting review of this just recently in March 2004 in Clinical Infectious Diseases where they actually proposed the hypothesis that no drug is really all bactericidal or all bacteriostatic, that the way in which we define these things is really 80 percent or so killing with a bacteriostatic and 99 percent of so with bactericidal and that, by altering the conditions of inoculum, pH, et cetera, that you can actually alter whether a drug is bacteriostatic or bactericidal in the test tube.

         The real question, though, is what is the clinical significance of bactericidal versus bacteriostatic.  We have all been taught that, in serious diseases where the antibiotic may not penetrate or there is little help from the host immune system such as meningitis and endocarditis, that at least, in animal models, it appears that bactericidal drugs look more effective in those models.

         So the question is what do you do, then, with a drug that appears bacteriostatic in the test tube.  Would that be something that folks would be able to study in this indication or could we use that staged approach that we talked about earlier.

         Again, could we look at, then, some animal models of infection to give us a better idea of how these drugs may work given that in vitro may not reflect clinical outcomes perfectly and what kind of animal models would we need.  Endocarditis would seem to be an obvious one but are there other potential metastatic sites of infection like bone that we would want to look at animal models as well.

         (Slide.)

         Then what clinical experience would be helpful in evaluating a new drug for this indication?  We know that spontaneous generation in the bloodstream was done away with a number of years ago as a potential reason why people have organisms so, obviously, these people have a primary site.  It is just that we don't find it.  So patients with no primary site, it is still coming from somewhere although it may be occult.

         The serious nature of this illness and, again, those potential differences in efficacy of drugs based on the primary site of infection, again, would weigh against this being the sole basis of approval for a new drug.

         So one of the things we would like the committee to address is what kinds of data from clinical trials of infections of sufficient severity where Staph aureus would be a potential pathogen would be helpful in evaluating in new drugs for this indication.

         Some of the ones we thought of were hospital-acquired pneumonia, community-acquired pneumonia sometimes especially after influenza outbreaks can occur due to Staph aureus, complicated skin and skin-structure infections and are there some others that the committee might suggest where Staph aureus is a common pathogen that we may be able to look at.

         So I would like to go into now a bit of--now that we have gone into the natural history of the disease, how will we actually design and analyze clinical trials for this indication.  One of the reasons we did the talks the way we did today was it is very important to look at the natural history of a disease and to design trials based upon that natural history.

         These clinical trials obviously need to provide information that is useful in clinical practice but it is a very important distinction to realize that clinical trials are not clinical practice.  We do lots of procedures to people in a clinical trial that are not routinely done in clinical practice but, perhaps, the biggest difference is that, in clinical practice, we give a drug and we don't care why the patient gets better as long as they recover.

         However, in a clinical trial, what we are trying to do is to ascribe causality of results to the drug that was administered, a very different thing than what we do in clinical practice.  So, to allow us to do that, we use the scientific method and that is we hold as many factors constant as possible other than the drugs administered to the patients so that we can ascribe the causality of those results to those drugs that were administered.

         The Code of Federal Regulations actually says this in a very nice way.  It says; the purpose of performing any clinical investigation is to distinguish the effects of the drug from other influences such as spontaneous change in the course of the disease, placebo effect or biased observations.  There are a number of other things such as potential confounders that may come into the trial like concomitant medications, et cetera, that also impact on that as well.

         (Slide.)

         So I wanted to sort of show this as a map and talk about the places where potential bias may creep into a trial and then try to address some of these in terms of primary bacteremia due to Staph aureus indication.

         So what we first do is we obviously take a group of people as a whole who have the disease or even, more importantly, that we think might have the disease and then try to define the patients who would enter into the trial.  Clearly, the first step there is we want to make sure they have the illness that we are trying to study.

         The issue here, too, is that this population needs  to be heterogeneous enough to extrapolate to the people we are going to treat in practice but homogeneous enough to be able to make some conclusions about drug efficacy.  Then we randomize people and, hopefully, blind this as well, talk about things that may occur while patients are on therapy, appropriate endpoints and how we analyze the data.

         (Slide.)

         So the first issue there is defining the patients who would actually come into the trial which is based upon the inclusion and exclusion criteria.  Again, as I said, we need to strike a balance between a homogeneous enough population to study so that outcomes are not related to the differences in the natural history of the disease just like the Code of Federal Regulations said we are not trying to measure and that they are related to drug effects, but has to be heterogenous enough to be able to extrapolate this to clinical practices.

         One of the first issues is we would need to differentiate among patients with Gram-positive cocci in the blood.  Dr. Murray gave us a good talk this morning about how we may be able to do this.

         One of the issues we have seen is that if you go to the microbiology laboratory and try to use that as the way to screen for patients in these trials, what is going to happen is, a, you are going to get a lot of Staph epidermidis and, even if they have Staph aureus, those people are likely to have received some amount of therapy by the time you get back to the patient who is up on the floor.

         So the question we like to ask the committee here is are there better ways of screening for patients than just getting the breakdown of who comes out of the microbiology lab.  More and more, as we see these trials, we are beginning to see that especially in shorter-term illnesses that that one or two days of antibiotic that people get up front may have a big influence on the outcome at the other end.  So that may not be an insignificant problem.

         Again, these newer diagnostic tests that Dr. Murray talked about may allow us to differentiate Staph epidermidis from Staph aureus prior to enrollment which would be a huge benefit because, otherwise, the drop-out rate from these trials may be considerable.

         (Slide.)

         Again, we know that there are different natural histories for various populations of patients in whom subsequent testing after randomization may show a source or a metastatic site of infection, such as endocarditis.  Again, I mentioned the difference success rates and the different durations of therapy that may be necessary depending upon what infection site the patient ultimately has although it may be difficult prior to enrollment to differentiate those people.

         As Dr. Nambiar presented, even patients with what may be considered uncomplicated disease such as catheter-related infections may subsequently develop metastatic disease.  So all of these things we are looking at are risk factors for metastatic illness but does not obviate that the patient may then develop those sites of infection on therapy.

         (Slide.)

         One of the things that we always find very important at the FDA is what you call something and the name of an indication.  So I wanted to be clear about some of the definitions that we are using here today.  One of them was complicated versus uncomplicated disease.  Again, looking through the literature, we found various definitions of what you would call this.  In fact, in the study by Small and Chambers that Dr. Tally referred to, what we found is that what they called complicated was just somebody that continued to have fever which is a very different issue than what we saw as complicated in some other trials.

         So what we put out as a trial definition for you folks to discuss is complicated disease would be patients who develop further clinical manifestations that were not present at the time of initial diagnosis that may portend a worse prognosis and/or need for prolonged therapy.

         As Dr. Nambiar said, these can be divided into two categories; severe sepsis, ARDS and DIC which usually occur within 48 hours but then that issue of metastatic sites of infection which may occur early on, may occur later, and some preliminary evidence that we found says may actually decrease with the institution of effective therapy.  But you saw the limitations of the data that we were able to find.

         What we haven't really found to be very useful is this distinction between community-acquired versus nosocomially-acquired infections.  When we look through the literature, what we saw is this really wasn't referring to the geography of where you got the infection.  It was really trying to refer to different host populations.

         Although we have defined community-acquired versus nosocomial with diseases like pneumonia, the question is does it really help us here.  When we went back and analyzed our data from the Focus Technologies database, we saw that these PVL-containing community-acquired MRSAs which usually remain susceptible to clindamycin, tetracycline and trimethoprim sulfa were really mixed in with the multi-drug-resistant Staph aureus that you would normally think of as nosocomial when we evaluated only outpatient isolates of Staph aureus.

         So what that tells us is sicker people are going home, getting mixed up out there in the community with the people who have community-acquired MRSA and so, when somebody gets sick in the outpatient setting, which one of those do they have.  It is not really the fact that they got it as an outpatient that determines what is happening.  It is really the host factors that determine it.

         So our looking at this says this may not be as useful a distinction in clinical trials for labeling given that there is such overlap in the populations.  If we tell a clinician, use this for community-acquired and that is a dialysis patient who is in and out of the hospital every day, that becomes very confusing to the clinician.

         (Slide.)

         So one of the issues here, obviously, is it is very difficult to stratify these patients at the time of enrollment.  We brought up this morning this issue of could you wait a little while, see what happens to these patients and then treat them later.  Well, that data that shows that DIC, ARDS and severe complications can occur within 48 hours would really argue against waiting for any period of time.

         But, since we can't wait, these metastatic complications may occur after enrollment.  So, how well do these risk factors that have been cited in the literature select patients who have complicated disease and uncomplicated and, therefore, with uncomplicated, could these people receive what has been called short-course therapy.

         Nathan Fieldman and I did our fellowship at Virginia.  One of our co-fellows, John Jernigan, did a study while we were there, or a meta-analysis, looking back at all the studies that have been in the literature up to that point in time on evaluating short-course therapy for Staph aureus bacteremia.

         What John and Barry Farr found was that many of these studies differentiating complicated from uncomplicated infection were retrospective and 10 of the 11 trials that they looked at that time were uncontrolled.  It is very difficult to be able to make any real good assumptions about whether short-course versus long-course has any differences associated with it.

         We, then, went back and tried to pull all the studies from 1993 to the present to see if there were any differences and all we found, again, was either observational studies or retrospective studies.  So, again, even since 1993, there is not much new information that would allow us to be able to draw any firm conclusions about short-course therapy in this disease even if you had uncomplicated disease.

         So one of the questions we are going to ask the committee today is how do we deal with that in terms of setting the duration of therapy.

         (Slide.)

         How useful are these risk factors that have been enumerated in the literature in the past in the clinical-trials setting.  Well, these may be useful in clinical practice but some of these risk factors, like duration of fever and duration of bacteremia actually occur after the patient has been randomized.

         The other thing is these are all based upon the fact the you have a known effective drug.  So, if a person is on nafcillin and remains bacteremic for three or four days, you could say, well, I think that person has endocarditis but I feel comfortable leaving them on nafcillin.  This is a different situation where we are now testing an experimental drug in this setting, so does duration of fever and of bacteremia say something about how well the drug is working.

         So how could we then use an outcome to define who the patients are at the beginning of the trial.  It seems like very circular reasoning.

         (Slide.)

         The other issue I wanted to bring up is, since these risk factors are based on outcomes with known effective therapy--I brought that up already about experimental drugs--how should patients who develop a site of infection after randomization be handled.  I think Dr. Fleming asked this question earlier.  Could patients with no signs or symptoms at the primary site be left in the trial when they develop a site of infection on therapy and does that have something to do with the timing of when they develop that site of infection.

         So, if a person ends up in the trial and, within three or four days, develop pneumonia, can we assume that that pneumonia was there?  If they develop pulmonary emboli, does that mean it was there at the time?  Even if it was there at the time, should we still call those people failures of therapy in order to actually analyze people evenly between the arms of the trial.

         In the past, we have evaluated--in empiric febrile neutropenia trials, we have set a breakpoint of calling people baseline versus breakthrough infections.  But that presents another conundrum.  If you set that breakpoint, suppose somebody gets the infection one day before versus the person who gets an infection one day after that breakpoint.  Are those people really different.  That is a real conundrum we are going to ask you to comment on today.

         What is really important here, though, is patients would need some kind of standardized evaluation at the time of enrollment so that there are no potential differences between arms of the study in determining who has baseline infections and who does not.

         So, if one study center decides, we are only going to do chest X-rays and another study center says, we are going to do chest X-rays, bone scans and CAT-scan everybody from head to toe, the total body "groapgram," then how would we match those two up.  So there would need to be some standardized way.  We realize you have to be practical about what you can do here and that we can't ask for every test in every person.

         But, as Dr. Nambiar pointed out this morning, that one study actually showed that you find what you look for.  The harder you look, the more likely you are to find the primary site of infection.

         So we are going to ask you today what tests would be appropriate and, given this issue that endocarditis is such a concern, would every patient need some kind of echocardiography to evaluate those patients for endocarditis given that even patients with catheter-related bacteremias may go on to develop subsequent endocarditis.

         (Slide.)

         So, again, should patients who develop a site of infection be considered clinical failures on therapy?  Should one differentiate baseline from breakthrough infections?  And, again, can that be part of what we consider as part of the endpoints in this disease.

         When we actually evaluated this, and I will go back to the paper that Dr. Tally brought up by Small and Chambers that was published in Antimicrobial Agents and Chemotherapy in 1990.  What they did was they took patients and, if their blood cultures were negative, and yet they remained persistently febrile, they called those people failures.

         If they had some other complication, even in the face of a negative blood culture, they were called failures.  It is interesting that we use that data to say vancomycin may not be so effective.  But now, when we are talking about clinical trials on the other end, how are we going to handle that and call those people.

         So it seems, when we were discussing this, that a negative blood culture doesn't always tell you that the person is not going to go on to have some clinical complication down the line.  So would a proper endpoint include not only negative cultures, which we clearly think are important, but also some other evaluation of how the patient is actually doing down the line.

         The other issue is this idea of time to negative blood cultures.  This has been commented on several times in the literature and probably goes back originally to the Kourzanowski paper in the Annals of Internal Medicine in 1982 wherein patients with right-sided endocarditis, they tested nafcillin plus gentamicin versus nafcillin alone.

         I put this in my category of urban legends of infectious diseases because we are always told that we should use gentamicin up front for the first five days.  The first issue is that is now how the study was done because the patients got gentamicin plus nafcillin all along during the therapy and what they showed was that, in a subgroup analysis of only non-addicts, eliminating all the addicts, which consists of 11 patients on nafcillin and 19 on the combination, they showed 3.4 days of bacteremia in nafcillin and 2.9 days in nafcillin plus gentamicin.

         A, is that a real difference anyway that is clinically significant, about a half a day's worth of difference and then, after that trial was done, people say, well there was more toxicity in the gentamicin arm, obviously renal insufficiency.  They said, well, since it causes renal insufficiency, let's just give the gentamicin for five days up front.

         And that is what we recommend.  And that is actually recommended in the American Heart Association guidelines.  But that is not how it was studied.  So that becomes an issue, too, for selecting control regimens which we will get to down the line.

         But the real point here, in terms of this problem here, is that time to negative cultures didn't correlate with either morbidity or morality in that Kourzanowski study.  So, even if you can make the blood cultures turn negative faster, what does it mean clinically for the  patient down the line.

         (Slide.)

         The next issue is how should the duration of therapies in studies of this indication be determined.  The first question is why is that even important to discuss.  Again, the problem here is we leave this up to investigator discretion, we may introduce a potential bias that similar groups of patients may be being treated with two weeks worth of treatment at one center and four weeks worth of treatment in the other and how would we compare those.

         So this is a big issue because we know that there is significant variation in clinical practice even for uncomplicated disease.  I know every time we brought this up when I was a fellow and we would have a Monday conference about this, the attendings would be throwing stones at each other back and forth about whether everybody should get four weeks regardless just because they have Staph aureus in their blood versus others who thought that you could select a population that should get shorter-course therapy.

         In the terms of clinical trial, this would really need to be specified up front as to what duration of therapy would be appropriate for what patients.

         (Slide.)

         So the next question is how would appropriate control regimens be designed for this indication.  Let me go back, since I didn't hear this until Dr. Tally presented his, I want to talk a little bit about this vancomycin versus nafcillin distinction.

         When we went back and actually looked through this data, there are no randomized controlled trials that actually compare those.  The first study or the most recent one is the one by Chang which was published in Medicine in 2003.  The problem there is that we need to really understand the limitations of some of this data.

         While that study evaluated 505 patients in a prospective manner, it was an observational trial.  An observational trial is not randomized and the problem with that is that it may not, then, account for some of the differences between the patient populations.  Since it is also observation, they have no influence on how the patients actually are treated which means that things like management of the catheter is not controlled for in that population.

         So what they did, then, was come up with a relative risk for vancomycin.  It doesn't mean that vancomycin is inferior because there is no direct comparison between vancomycin and nafcillin within that trial.  So, again, there are some limitations in looking at that.

         The study by Small and Chambers published in 1990 in Antimicrobial Agents and Chemotherapy evaluated all of 13 patients who received vancomycin and they were I.V.-drug abusers.  Five of those 13 patients were considered failures.  And, again, we know that 100 percent of patients are not cured when they have endocarditis.  So what you really need is some control, which that trial did not have.

         What they then did was they went back and they pulled several papers which had essentially between 10 and 25 patients, pooled them all together and t